CN114096565A - Pip4k通过非催化依赖性机制抑制胰岛素信号传导并增强免疫功能 - Google Patents
Pip4k通过非催化依赖性机制抑制胰岛素信号传导并增强免疫功能 Download PDFInfo
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Abstract
如本文所述，磷脂酰肌醇‑5‑磷酸4‑激酶(PIP4K)除了具有催化活性，还具有变构功能。所述变构功能能够抑制PIP5K介导的PI(4,5)P2合成和胰岛素依赖性转化为PI(3,4,5)P3。本发明进一步描述了用于治疗糖尿病、代谢综合征、胰岛素抵抗、肥胖症、癌症、免疫缺陷、自身免疫性疾病、感染或其组合的方法。
Description
本申请请求于2019年4月10日提交的第62/831,895号美国临时申请以及于2019年5月14日提交的第62/847,411号美国临时申请的申请日优先权的权益，所述美国临时申请的内容通过本发明的整体引用，成为本发明的一部分。
政府资助
本发明接受了美国国立卫生研究院(National Institutes of Health)授予R35CA197588、U54CA210184的政府支持。政府对本发明享有某些权利。
序列表
本申请包含了已经以ASCII格式通过EFS-Web递交的序列表，该序列表通过本发明的整体引用，成为本发明的一部分。所述ASCII副本的创建时间为2020年4月9日，命名为2029260.txt，大小为81920字节。
背景技术
在细胞调节过程中，磷脂酰肌醇-4,5-二磷酸酯(PI(4,5)P2)发挥着诸多作用。它能够介导质膜部位的肌动蛋白重塑、调节囊泡运输，激素刺激的磷脂酶C(PLC)利用PI(4,5)P2作为底物，生成第二信使二酰基甘油和肌醇-1,4,5-三磷酸酯(Balla，《生理学评论(Physiol Rev)》，93:1019-1137(2013)；Sun等人，《生物学论文集(Bioessays)35:513-522(2013)。PI(4,5)P2还是1类磷酸肌醇3-激酶(Saito等人，《免疫(Immunity)19:669-678(2003)为了响应胰岛素和其它生长因子而生成第二信使磷脂酰肌醇-3,4,5-三磷酸酯(PI(3,4,5)P3)时所使用的底物(Fruman等人，《细胞(Cell)170:605-635(2017)。
酵母中含有一种酶，用于生成由MSS4编码的PI(4,5)P2，而哺乳动物体内含有六种基因编码酶，用于生成PI(4,5)P2。PIP5K1A、PIP5K1B和PIP5K1C从磷脂酰肌醇-4-磷酸酯(PI(4)P)中产生PI(4,5)P2，而PIP4K2A、PIP4K2B和PIP4K2C从磷脂酰肌醇-5-磷酸酯(PI(5)P)中生成PI(4,5)P2：(Rameh等人，《自然(Nature)》390:192-196(1997；van den Bout&Divecha，《细胞科学杂志(J Cell Sci)》122:3837-3850(2009)。
有推测认为，PIP4K的功能主要是降低PI(5)P的水平(Jones等人，《分子细胞(MolCell)》23:685-695(2006)；Wilcox和Hinchliffe，《欧洲生化学会联合会快报(FEBS Lett)》582，1391-1394(2008)。尽管PIP4K家族成员具有合成PI(4,5)P2的酶功能，但其还可以在体内抑制胰岛素/PI3K/mTORC1信号传导。小鼠中的Pip4k2b-/-纯合性种系缺失具有减肥的作用，增加了肌肉中的胰岛素敏感性(Lamia等人，《分子细胞生物学(Mol Cell Biol)》24，5080-5087(2004)，并且Pip4k2c-/-小鼠具有增强的TORC1信号传导作用(Shim等人，2016)。另外，由于高活性形式PIP4K的丢失引起了PI(5)P积聚，增加了通过PI3K路径进行的信号传导(Carricaburu等人，《美国国家科学院院刊(Proc Natl Acad Sci U S A)》100:9867-9872(2003)；Pendaries等人，《欧洲分子生物学学会杂志(EMBO J)》25:1024-2034(2006)。
发明内容
尽管PIP4K蛋白似乎参与了各种细胞活动，但出于治疗目的而进行的多项药剂开发工作并未取得成功，这些药剂能够成功调节PIP4K的表达和功能，例如已经尝试开发的PIP4K催化位点抑制剂，但是如本文所示，催化位点抑制剂不会引起PI3K信号传导的改变。
如本文所述，PIP4K通过酶活非依赖的方式调节细胞和下游信号传导路径(AKT，PRAS40)中的PI3K信号传导，激活免疫细胞活化路径。尽管PIP4K可以催化从磷脂酰肌醇-5-磷酸酯(PI(5)P)中产生磷脂酰肌醇-4,5-二磷酸酯(PI(4,5)P2)的过程，但PIP4K还具有影响胰岛素敏感性、肥胖和免疫应答的结构作用或支架作用。例如，PIP4K可以与其它PIP4K和磷脂酰肌醇-4-磷酸5-激酶(PIP5K)相互作用或形成支架。
本文提供了用于降解、修饰或抑制磷脂酰肌醇-5-磷酸4-激酶(PIP4K)的一种或多种异构体的方法和组合物。此类方法和组合物可以增强受试者中的胰岛素信号传导、降低胰岛素抵抗和/或增强免疫功能。
以此方式降解、修饰或抑制的磷脂酰肌醇-5-磷酸4-激酶可以是PIP4K2A、PIP4K2B、PIP4K2C或其组合。
附图说明
图1A-1O展示了所有三种磷脂酰肌醇5-磷酸4-激酶(PIP4K)异构体的消除工具的验证情况，结果表明，磷脂酰肌醇-4,5-二磷酸酯(PI(4,5)P2)水平出现了反常升高。图1A示出了蛋白印迹的图像，所述图像展示了Hela细胞中PIP4K异构体的敲减效率。表4中列出了细胞系符号及其描述。图1B示出了蛋白印迹的图像，所述图像展示了293T克隆中的PIP4K异构体表达，以及CRISPR介导的PIP4K2A、PIP4K2B和PIP4K2C敲除。细胞系描述如表4所示。亲本细胞系在第一泳道中，并且具有完整PIP4K的CRISPR克隆细胞系采用WT设计。刚好可以看到微弱的非特异性条带，其运行速度稍快于PIP4K。图1C以图形方式展示了通过HPLC确定的磷脂酰肌醇-5-磷酸(PI(5)P)水平，表明细胞内PI(5)P增加，减少了PIP4K2A/B/C三重敲减(TKD1或TKD2，见表4)Hela细胞中的PIP4K。图1D以图形方式展示了通过HPLC确定的磷脂酰肌醇-5-磷酸(PI(5)P)水平，表明细胞内PI(5)P增加，减少了PIP4K2A/B/C三重敲减(TKO1或TKO2，见表4)293T细胞中的PIP4K。图1E示出了蛋白印迹的图像，所述图像展示了PIP4K敲减增强了Hela细胞中的胰岛素信号传导。通过Licor对pAkt-473条带进行量化，在相应的泳道下方表示。图1F展示了溶酶体标志物Lamp1的免疫荧光检测情况，其展示了相对于对照细胞，293T TKO中的Lamp1溶酶体积聚增加。代表性图像如图所示。图1G展示了细胞中PI(4,5)P2的增加以及PIP4K的丢失，如Hela TKD细胞所示，该测量结果通过HPLC得出。图1H展示了细胞中PI(4,5)P2的增加以及PIP4K的丢失，如293T TKO细胞所示，该测量结果通过HPLC得出。图1I展示了Hela TKD细胞中PI(4)P的减少，表明出现了PIP4K的丢失，该测量结果通过HPLC得出。图1J展示了293T TKO细胞中PI(4)P的减少以及PIP4K的降低，该测量结果通过HPLC得出。图1K展示了293T TKO细胞具有更高水平的PI(3,4,5)P3，该测量结果通过HPLC得出。利用方差分析(ANOVA)计算显著性，与具有完整PIP4K的对照细胞系进行Holm-Sidak多重比较。**p<0.01，***p<0.001，****p<0.0001。数据表示为平均值±SEM，n＝3。图1L-1O展示了多个PIP4K异构体的敲减。图1L为示意图，展示了多西环素诱导型载体(LG3GEPIR、LG3REPIR)或组成型载体(SGEP、SREN)中的miRE表达盒。发夹表达可以与GFP或红外RFP(iRFP)连环化。图1M展示了所有三种PIP4K异构体的shRNA介导敲减的动力学特征，其中细胞系描述见表4。在为期五天的多西环素治疗过程中，收获了表达多西环素诱导型发夹的293T细胞，并检测到PIP4K的异构体。图1N展示了293T细胞中PIP4K异构体的敲减验证情况。细胞系描述见表4。图1O以图形方式展示了72小时内的细胞增殖，用图形表示为平均汇聚+/-SEM(N＝6)。细胞系描述见表4。
图2A-2Z展示了PIP4K非催化依赖性功能的鉴定情况。图2A以图形方式展示了使用串联shRNA构建体敲减293T细胞中PIP4K的一种或多种异构体后，通过HPLC检测到的PI(4)P和PI(4,5)P2水平。发夹结构体在x轴上表示，其描述见表3-4。图2B以图形方式展示了在使用串联shRNA构建体敲减Hela细胞中PIP4K的一种或多种异构体后，通过HPLC检测到的PI(4)P和PI(4,5)P2水平。发夹结构体在x轴上表示，其描述见表3-4。图2C示出了蛋白印迹，提供了挽救细胞系组的验证情况，其中活性或激酶死亡PIP4K2AKD或活性PIP4K2C以近内源性水平重构到Hela TKD细胞中。用三个血凝素标签(3xHA-PIP4K蛋白)标记的PIP4K大于内源性蛋白。可以看到，微弱非特异性条带的运行速度稍快于内源性蛋白。图2D示出了蛋白印迹，提供了挽救细胞系组的验证情况，其中活性或激酶死亡PIP4K2AKD或活性PIP4K2C以近内源性水平重构到293T TKO细胞中。标签3xHA-PIP4K蛋白大于内源性蛋白。可以看到，微弱非特异性条带的运行速度稍快于内源性蛋白。图2E以图形方式展示了通过HPLC评估的HelaTKD挽救细胞系中的PI(4,5)P2水平。图2F以图形方式展示了通过HPLC评估的293T TKO挽救细胞系中的PI(4,5)P2水平。图2G以图形方式展示了通过HPLC评估的Hela TKD挽救细胞系中的PI(4)P水平。图2H以图形方式展示了293T TKO挽救细胞系中的PI(4)P水平。图2I以图形方式展示了Hela TKD挽救细胞系中的PI(5)P水平。图2J以图形方式展示了293T TKO挽救细胞系中的PI(5)P水平。对于图2E-2J，利用ANOVA计算显著性，与TKD或TKO细胞系进行Holm-Sidak多重比较。*p<0.05，**p<0.01，***p<0.001，****p<0.0001，数据表示为平均值±SEM，n＝3。图2K-2Z展示了各种组织和突变背景的细胞系组中的PIP4K耗尽情况。图2K展示了根据癌细胞系百科全书(Cancer Cell Line Encyclopedia)的报告，PIP4K2A、PIP4K2B和PIP4K2C在发生突变的PaTu 8988t细胞系中的敲减(TDK)。图2L展示了根据癌细胞系百科全书的报告，PIP4K2A、PIP4K2B和PIP4K2C在发生突变的H1299细胞系中的敲减(TDK)。图2M展示了根据癌细胞系百科全书的报告，PIP4K2A、PIP4K2B和PIP4K2C在发生突变的H1975细胞系中的敲减(TDK)。图2N展示了根据癌细胞系百科全书的报告，PIP4K2A、PIP4K2B和PIP4K2C在发生突变的MCF7细胞系中的敲减(TDK)。图2O展示了PIP4K2A、PIP4K2B和PIP4K2C在BJ永生化成纤维细胞中的敲减(TDK)。图2P展示了根据癌细胞系百科全书的报告，PI(4,5)P2/PI在发生突变的PaTu 8988t细胞系中的表达。图2Q展示了根据癌细胞系百科全书的报告，PI(4)P/PI在发生突变的PaTu 8988t细胞系中的表达。图2R展示了根据癌细胞系百科全书的报告，PI(4,5)P2/PI在发生突变的H1299细胞系中的表达。图2S展示了根据癌细胞系百科全书的报告，PI(4)P/PI在发生突变的H1299细胞系中的表达。图2T展示了根据癌细胞系百科全书的报告，PI(4,5)P2/PI在发生突变的H1975细胞系中的表达。图2U展示了根据癌细胞系百科全书的报告，PI(4)P/PI在发生突变的H1975细胞系中的表达。图2V展示了根据癌细胞系百科全书的报告，PI(4,5)P2/PI在发生突变的MCF7细胞系中的表达。图2W展示了根据癌细胞系百科全书的报告，PI(4)P/PI在发生突变的MCF7细胞系中的表达。图2X展示了PI(4,5)P2/PI在BJ永生化成纤维细胞中的表达。图2Y展示了PI(4)P/PI在BJ永生化成纤维细胞中的表达。图2Z以图形方式展示了不同细胞系中PI(4)P/PI与PI(4,5)P2/PI的比率。
图3A-3Q展示了PIP4K能够抑制PIP5K活性。图3A以图形方式展示了PIP5K活性在具有TKO基因型的293T细胞中的变化。根据细胞数使细胞团块正常化，并在过量PI(4)P存在的情况下，对细胞团块进行声波处理。添加放射性ATP32进行激酶反应。二酰化后，通过TLC提取脂质并量化，并通过HPLC确认。图3B以图形方式展示了体外激酶测定的量化情况，该测定通过PIP5K1A测量了PI(4)P到放射性标记PI(4,5)P2的转化。通过添加2-10倍摩尔过量PIP4K2A、PIP4K2B或PIP4K2C，对PIP5K1A活性进行体外抑制。图3C以图形方式展示了一旦变性，PIP4K2C就不再抑制PIP5K1A。图3D以图形方式展示了在0.1％Triton-X100存在的情况下，PIP4K2A不再抑制PIP5K1A活性。图3E示出了蛋白印迹，提供了293T对照和PIP5K1A TKO细胞中3xHA-PIP5K1A水平的近内源性水平表达的验证情况。标记3xHA-PIP5K1A略大于内源性蛋白。图3F展示了使用来自表达空3xHA载体(空)或3xHA-PIP5K1A(PIP5K1A)的293T WT细胞的抗HA磁珠的拉下。蛋白印迹示出了输入(前两条泳道)和具有PIP5K1A的免疫沉淀内源性PIP4K2A(后两条泳道)。图3G示出了通过蛋白印迹检测到的强拉下蛋白，以检测PIP5K1A和PIP5K1C的富集情况。将293T裂解物与用GST或GST-PIP4K2C预培养的磁珠一起培养，用作诱饵。图3H展示了图3G中所述拉下实验的流通情况，以示出裂解物被诱饵耗尽PIP5K1A和PIP5K1C的程度。图3I展示了PIP4K中N端区域的序列同源性。PIP4K2C aa69-75的突变残基用红色下划线表示。PIP4K2A肽序列INELSHVQIPVMLMPDDFKAY SKIKV具有SEQ ID NO:1。PIP4K2B肽序列INELSNVPVPVMLMPDDFKAYSKIKV具有SEQ ID NO:2。PIP4K2C肽序列INELSQVPPPVMLLPDDF KASSKIKV具有SEQ ID NO:3。PIP4K2CVD肽序列INELSQVPPPEIFLPNNFKASSKIKV具有SEQ ID NO:4。图3J展示了通过蛋白印迹，对磁珠拉下进行分析，判断是否存在PIP5K1A，PIP5K1A能够结合WT PIP4K2C，但不能结合来自293T裂解物的PIP4K2CVD，所述裂解物与缀合到GST-PIP4K2C或GST-PIP4K2CVD并用作诱饵的磁珠一起培养。图3K以图形方式展示了体外激酶测定的结果，通过PIP5K1A对PI(4)P到放射性标记PI(4,5)P2的转化进行定量测量，所述转化受到PIP4K2C而非PIP4K2CVD的抑制。图3L以图形方式展示了由PIP4K2C和PIP4K2CVD挽救的HEK293T TKO细胞系中PI(4)P的数量，该测量结果通过HPLC得出。图3M以图形方式展示了由PIP4K2C和PIP4K2CVD挽救的HEK293T TKO细胞系中PI(4,5)P2的数量，该测量结果通过HPLC得出。对于图3L-3M，利用ANOVA计算显著性，并与对照细胞系进行Holm-Sidak多重比较。**p<0.01，****p<0.0001，n.s.为不显著。数据表示为平均值±SEM，n＝3。图3N-3Q展示了PIP4K改变PIP5K活性的机制。图3N以图形方式展示了PIP4K2AKD的表达引起磷脂酰肌醇脂质的剂量依赖性变化，示出了293T WT或TKO细胞中3xHA-PIP4K2AKD的低表达水平和高表达水平的验证情况。图3O以图形方式展示了PIP4K2AKD的表达引起磷脂酰肌醇脂质的剂量依赖性变化，示出了PIP4K2AKD低表达或高表达情况下的PI(4,5)P2测量值。图3P以图形方式展示了PIP5K活性的增加无法用磷脂酸的细胞水平予以解释。图3Q以图形方式展示了TKD1和TKD2细胞中的磷脂酸水平。
图4A-4K展示了PIP4K在PIP5K调节中的结构性作用，PI3K路径不同于其在自噬中的催化作用。图4A以图形方式展示了根据HPLC的量化结果，293T挽救细胞系中PI3K对PI(3,4,5)P3合成的胰岛素刺激。对细胞进行20小时的血清饥饿处理，然后进行5分钟的50ng/mL胰岛素刺激。图4B示出了蛋白印迹，展示了Hela挽救细胞系组中Akt活化的胰岛素刺激。对于图4A-4B，对细胞进行12小时的血清饥饿处理，然后进行10分钟的250ng/mL胰岛素刺激。通过Licor测量蛋白印迹条带强度，并用相关条带下面的数字表示。图4C以图形方式展示了不同Hela挽救细胞系中受胰岛素刺激的pAkt-473增加情况，总Akt正常化，n＝3。图4D展示了对PIP4K催化活性的依赖性，以挽救293T挽救细胞系图像中增加的溶酶体积聚，其中，免疫荧光采用溶酶体标志物Lamp1。图4E以图形方式展示了在293T挽救细胞系中表达标志物Lamp1的溶酶体点的数量。图4F以图形方式展示了在通过293T挽救细胞系组中的qRT-PCR量化的TFEB靶向基因中，基因的基因表达水平。利用ANOVA计算显著性，与对照细胞系进行Holm-Sidak多重比较。*p<0.05，**p<0.01，***p<0.001，****p<0.0001，n.s.为不显著。图4G-4K展示了测试和表征PIP4K在抑制PIP5K方面的候选结构域。图4G以图形方式展示了根据体外激酶测定的量化结果，通过PIP5K1A进行的PI(4)P到放射性标记PI(4,5)P2的转化。在不存在或存在纯化PIP4K2C或截短PIP4K2C的情况下进行反应，氨基酸部位132(PIP4K2C*fs132)出现移码突变。图4H以图形方式展示了通过PIP5K1A进行的PI(4)P到放射性标记PI(4,5)P2的转化。在不存在或存在纯化PIP4K2C和点突变体PIP4K2C的情况下进行反应。利用ANOVA计算显著性，与对照细胞系进行Holm-Sidak多重比较，*p<0.05。图4I展示了PIP4K2CVD性质的验证。考马斯(Coomassie)证实了经细菌纯化的GST-PIP4K2C和GST-PIP4K2CVD的纯度、大小和丰度。图4J以图形方式展示了根据体外激酶测定的量化结果，PI(5)P到放射性标记PI(4,5)P2的转化，证实了GST-PIP4K2CVD的酶活性。图4K展示了对293T TKO细胞中3x标记PIP4K2C和PIP4K2CVD的近内源性水平表达的验证情况。
具体实施方式
如本文所示，PIP4K具有非催化功能，此功能涉及对其它细胞结构或蛋白的支架作用。支架作用功能解释了迄今为止PIP4K蛋白功能的几个容易混淆的方面，并且为各种疾病和病状提供了更成功的治疗方法和组合物。例如，靶向降解或耗尽PIP4K蛋白(PIP4K2A、PIP4K2B和PIP4K2C)可以调节细胞生长、代谢以及对外部刺激和生长信号的应答。例如，通过降解PIP4K，可以增加PI3K信号传导，从而增加胰岛素敏感性、降低循环葡萄糖水平并减少肥胖症。PIP4K蛋白在免疫细胞活化中也起到了一定作用。
降解或耗尽PIP4K蛋白可以改变免疫应答，免疫应答能够改变自身免疫性疾病的病程，并且改善感染或癌症应答。在一些情况下，可以向受试者施用降解或耗尽形式的PIP4K，以改变免疫应答，治疗各种疾病和病状。例如，本文所述的组合物和方法可以用于治疗糖尿病、代谢综合征、胰岛素抵抗、肥胖症、癌症、自身免疫性疾病、感染或其组合。
PIP4K2A酶、PIP4K2B酶和PIP4K2C酶
在细胞调节过程中，磷脂酰肌醇-4,5-二磷酸酯(PI(4,5)P2)发挥着诸多作用。它能够介导质膜部位的肌动蛋白重塑、调节囊泡运输，激素刺激的磷脂酶C(PLC)利用PI(4,5)P2作为底物，生成第二信使二酰基甘油和肌醇-1,4,5-三磷酸酯(Balla，2013；Sun等人，2013)。PI(4,5)P2还是1类磷酸肌醇3-激酶(Saito等人，2003)为了响应胰岛素和其它生长因子而生成第二信使磷脂酰肌醇-3,4,5-三磷酸酯(PI(3,4,5)P3)时所使用的底物(Fruman等人，2017)。
酵母中含有一种酶，用于生成由MSS4编码的PI(4,5)P2(Homma等人，1998)，而哺乳动物体内含有六种基因编码酶，用于生成PI(4,5)P2。PIP5K1A、PIP5K1B和PIP5K1C从磷脂酰肌醇-4-磷酸(PI(4)P)中产生PI(4,5)P2，而PIP4K2A、PIP4K2B和PIP4K2C从磷脂酰肌醇-5-磷酸(PI(5)P)中生成PI(4,5)P2(Rameh等人，1997；van den Bout和Divecha，2009)。所有多细胞生物体都具有来自这两个家族的基因。
由人PIP4K2A基因编码的人磷脂酰肌醇5-磷酸4-激酶2α型(异构体1)的序列实例如下文所示(SEQ ID NO:6，NCBI登录号：NP_005019.2)：
PIP4K N端基序VMLXPDD(SEQ ID NO:5，其中X为任何氨基酸)在SEQ ID NO:6中以粗体和下划线突出显示。在一些情况下，可以使基序VMLXPDD(SEQ ID NO:5)缺失或降解，以生成有用的PIP4K多肽。在其它情况下，具有VMLXPDD(SEQ ID NO:5)基序但没有PIP4K多肽的其它部分的PIP4K肽可能很有用。
编码具有(SEQ ID NO:6)的PIP4K2A蛋白的cDNA可以具有以下核酸序列(SEQ IDNO:7，NM_005028.5)。
存在PIP4K2A蛋白的其它异构体，这些异构体包含NCBI登录号：NP_001316991.1(GI:1052292374)；XP_006717513.1(GI:578818419)；XP_016871820.1(GI:1034568484)；XP_016871819.1(GI:1034568482)和XP_016871821.1(GI:1034568486)。可以修饰或靶向这些PIP4K2A蛋白中的任何蛋白，以降低其表达和/或降低其功能。
由人PIP4K2B基因编码的人磷脂酰肌醇5-磷酸4-激酶2β型的序列的实例如下文所示(SEQ ID NO:8，NCBI登录号：NP_003550.1)。
PIP4K N端基序VMLXPDD(SEQ ID NO:5，其中X为任何氨基酸)在SEQ ID NO:8中以粗体和下划线突出显示。如上文所示，在一些情况下，可以使基序VMLXPDD(SEQ ID NO:5)缺失或降解，以生成有用的PIP4K多肽。在其它情况下，具有VMLXPDD(SEQ ID NO:5)基序但没有PIP4K多肽的其它部分的PIP4K肽可能很有用。PIP4K2B蛋白在肌肉中的表达水平高于PIP4K2A或PIP4K2C在肌肉中的表达水平。因此，与通过靶向PIP4K2A或PIP4K2C进行降解相比，PIP4K2B的降解或耗尽可能对治疗胰岛素抵抗和肥胖症更有用。
编码具有(SEQ ID NO:8)的PIP4K2B蛋白的cDNA可以具有以下核酸序列(SEQ IDNO:9，NM_003559.4)。
存在PIP4K2A蛋白的其它异构体，这些异构体包含NCBI登录号：XP_011523628.1(GI:767996099)；XP_011523629.1(GI:767996101)；XP_011523632.1(GI:767996107)；XP_016880686.1(GI:1034601614)；和/或XP_016880688.1(GI:1034601618)。可以修饰或靶向这些PIP4K2B蛋白中的任何蛋白，以降低其表达和/或降低其功能。
由人PIP4K2C基因编码的人磷脂酰肌醇5-磷酸4-激酶2γ型的序列的实例如下文所示(SEQ ID NO:10，NCBI登录号：NP_079055.3)。
PIP4K N端基序VMLXPDD(SEQ ID NO:5，其中X为任何氨基酸)在SEQ ID NO:10中以粗体和下划线突出显示。在一些情况下，可以使基序VMLXPDD(SEQ ID NO:5)缺失或降解，以生成有用的PIP4K多肽。在其它情况下，具有VMLXPDD(SEQ ID NO:5)基序但没有PIP4K多肽的其它部分的PIP4K肽可能很有用。
PIP4K2C蛋白在免疫细胞中的表达水平高于PIP4K2A或PIP4K2B在免疫细胞中的表达水平。因此，与通过靶向PIP4K2A或PIP4K2B进行降解相比，PIP4K2C的降解或耗尽可能对治疗免疫系统病状和癌症更有用。
编码具有(SEQ ID NO:10)的PIP4K2C蛋白的cDNA可以具有以下核酸序列(SEQ IDNO:11，NM_024779.5)。
存在PIP4K2C蛋白的其它异构体，这些异构体包含NCBI登录号：NP_001139730.1(GI:226371739)；NP_001139731.1(GI:226371741)；NP_001139732.1(GI:226371743)；XP_005269209.1(GI:530400838)；XP_011537049.1(GI:767975336)；和/或XP_016875462.1(GI:1034581618)。可以修饰或靶向这些PIP4K2C蛋白中的任何蛋白，以降低其表达和/或降低其功能。
与本文所述的序列相比，PIP4K2A酶、PIP4K2B酶和PIP4K2C酶可以具有一个或多个氨基酸差异。例如，受试者可以具有变体PIP4K2A、PIP4K2B或PIP4K2C酶序列，所述酶序列与本文所述的PIP4K2A、PIP4K2B或PIP4K2C氨基酸序列中的任何氨基酸序列具有至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少99％的氨基酸序列一致性或相似性。类似地，与本文所述的PIP4K2A、PIP4K2B或PIP4K2C核酸相比，受试者可以具有带有一个或多个核苷酸差异的PIP4K2A、PIP4K2B或PIP4K2CRNA。例如，受试者可以表达与本文所述的PIP4K2A、PIP4K2B或PIP4K2C核酸序列具有至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少99％氨基酸序列一致性或相似性的PIP4K2A、PIP4K2B或PIP4K2C RNA。
由这两个基因家族编码的酶具有序列和结构相似性，但PIP4K的活化环赋予了PI(5)P优于PI(4)P的严格底物选择性(Kunz等人，2001；Kunz等人，2000a)。
在已经进行磷酸肌醇量化的环境中，PI(4)P和PI(4,5)P2各自占总细胞磷酸肌醇的30-50％。然而，在用生长因子或激活PLC或PI3K的激素对细胞进行刺激时，PI(4,5)P2的局部水平可能会暂时下降，PI(4,5)P2和PI(4)P的总体水平保持非常恒定。在细胞中，PI(4)P比PI(5)P丰富100多倍，并且通常假设哺乳动物细胞中的大多数PI(4,5)P2从PI(4)P中通过PIP5K生成(Balla，2013)。在B细胞活化过程中，PIP5K1A的瞬时募集对于生成PI(3,4,5)P3进行信号转导十分有必要(Saito等人，2003)。
PI(5)P约占细胞磷酸肌醇的1％，所以不确定这种脂质是否对总细胞PI(4,5)P2有实质性的贡献，从而提出了对PIP4K的功能主要是降低PI(5)P水平的推测(Jones等人，2006；Wilcox和Hinchliffe，2008)。本发明人最近的工作表明，需要通过PIP4K2A/2B(可能在溶酶体上)将PI(5)P转化为PI(4,5)P2来介导自噬体和溶酶体之间的融合(Lundquist等人，2018)。这项研究认为，虽然PIP4K仅生成了一小部分细胞PI(4,5)P2，但这些酶生成的PI(4,5)P2的位置在自噬完成中发挥了重要作用。还有证据表明，质膜、高尔基体(Golgi)和细胞核中存在PIP4K2A/2B/2C池，因此PIP4K酶很可能具有自噬调节以外的许多其它功能(Bultsma等人，2010；Jones等人，2006；Mackey等人，2014)。
总的来说，尚不清楚膜脂质的变化如何构成PIP4K调节PI3K路径的分子机制的基础，并且尚不清楚一种PIP4K异构体是否可以补偿其它异构体，以抑制生长因子信号转导。
如本文所示，PIP4K在控制细胞代谢方面具有截然不同的催化功能和非催化功能，并且正是PIP4K非催化依赖性功能的丢失构成了增强胰岛素信号传导的基础。
PIP4K2A和PIP4K2B异构体在自噬体-溶酶体融合中的作用取决于这些酶将PI(5)P转化为PI(4,5)P2的能力。然而，本文所述的实验表明，先前在Pip4k2b-/-小鼠中观察到的胰岛素敏感性增加(Lamia等人，2004)，其原因在于PIP4K2B在抑制PIP5K产生用作PI 3-激酶底物的PI(4,5)P2的能力方面的非催化功能的丢失。一个令人困惑的问题可能是，当PIP4K耗尽时，可以观察到PI(5)P增加。先前表征Ipgd(即PI(4,5)P2的细菌4-磷酸酶)的研究证明，增加PI(5)P水平可以延长Akt信号传导(Carricaburu等人，2003；Niebuhr等人，2002；Pendaries等人，2006)。Carricaburu等人提出的模型描述了增加的细胞PI(5)P如何抑制PI(3,4,5)P3特异性磷酸酶，由此导致PI(3,4,5)P3水平升高。这表明在某些环境中，PIP4K的催化活性可以通过控制PI(5)P水平来调节Akt信号传导。
然而，本文提供的数据表明，尽管没有降低PI(5)P，但是作为对胰岛素信号传导的响应，通过激酶死亡PIP4K进行重建可以完全挽救PI(3,4,5)P3水平和Akt磷酸化作用，表明PIP4K具有本领域目前不了解的功能。
而且，如本文所示，PIP4K和PIP5K之间直接相互作用，使PIP4K2C的五个保守氨基酸突变可以消除此相互作用，并防止PIP5K抑制。在调节PIP5K活性方面的作用阐明了细胞中PIP4K高度丰富的原因，PIP4K的丰富程度超过了被认为产生大多数PI(4,5)P2的PIP5K。因为PIP4K和PIP5K均与带负电荷的膜结合，这些酶还可以改变局部膜结构或募集其它酶来修饰PIP5K，以进一步调节其活性。
本文所示的结果表明，可以使PIP4K降解的方法和组合物可以减轻胰岛素抵抗，并延缓II型糖尿病的进展。例如，特定PIP4K蛋白可以通过与E3连接酶连接而发生降解(Bondeson和Crews，2017)。
由于PIP4K2B/2C或PIP4K2A/2B种系共缺失的胚胎致死性，本发明人最初对此类药物的开发持保留意见(Emerling等人，2013；Shim等人，2016)。另外，根据Emerling等人，2013和Lundquist等人，2018的报告，在p53信号传导不足的细胞系中，PIP4K2A/2B丢失后，小鼠胚胎成纤维细胞的活力有所降低(Emerling等人，2013、Lundquist等人，2018)。
然而，本文所示的关于癌症系组的结果表明，在具有全部营养物的组织培养物中生长时，大多数细胞系无需PIP4K异构体即可获得活力(图2K-2Z)。由于小鼠PIP4K异构体共缺失导致的胚胎致死性可能归因于哺乳动物发育所需的发育缺陷或围产期的养分胁迫(Emerling等人，2013；Shim等人，2016)，并且部分和/或组织特异性靶向耗尽可能具有良好的耐受性。
PIP4K家族成员抑制PI(4)P到PI(4,5)P2(并且随后到PI(3,4,5)P3)的转化，以限制PI3K路径信号传导。其发生机制不需要这些酶的催化活性，即使所述酶直接催化PI(5)P到PI(4,5)P2的转化以促进自噬。这两种不同的功能如何存在于同一蛋白质中？一种可能性是确保PI(4)P在自噬体-溶酶体融合的局部位点部位保持高水平。最近几项研究表明，自噬体-溶酶体融合需要PI(4)P，并且在一些情况下，此PI(4)P来源于作用于PI(4,5)P2局部池上的肌醇5-磷酸酶(De Leo等人，2016；Wang等人，2015)。因此，PIP4K既可以在自噬体-溶酶体连接部位产生局部PI(4,5)P2，又可以确保在转化为PI(4)P后，其不会通过PIP5K转化回PI(4,5)P2。此模型将确保PI(5)P到PI(4)P的单向转化以及高效自噬体-溶酶体融合。PIP4K2C在高尔基体上的局部定位(Clarke等人，2008)还可能抑制高尔基体PI(4)P到PI(4,5)P2的转化，以维持此部位囊泡运输所需的PI(4)P高局部浓度。
鉴于观察到PI(4,5)P2总体有所增加，毫无疑问，多个PI(4,5)P2介导功能将受到影响。表征PI(4,5)P2在PIP4K耗尽细胞中的积聚如何影响生长因子信号传导以外的细胞粘附、迁移和/或钙信号传导等细胞过程将会很有趣。进一步地，有必要检查此变化如何影响细胞内其它磷酸肌醇的定位和水平。
总之，本文所示的研究发现突出强调了PIP4K家族酶中催化功能和非催化功能的非预期和重要分离，并指出了在增强胰岛素信号传导、糖尿病、代谢综合征、胰岛素抵抗、肥胖症、癌症、自身免疫性疾病和感染方面的新型干预途径。
PIP4K2A、PIP4K2B和/或PIP4K2C蛋白的降解
尽管可以利用PIP4K2A、PIP4K2B和/或PIP4K2C基因敲减或敲除来减少这些蛋白质的细胞浓度或数量，但是最好在翻译后对PIP4K2A、PIP4K2B和/或PIP4K2C蛋白进行破碎、降解或不稳定处理。与通过编码蛋白的DNA或mRNA分子靶向蛋白相比，直接靶向蛋白法在减少PIP4K蛋白支架作用功能方面更为直接、快速。因此，降解可以允许进行某种PIP4K2A、PIP4K2B和/或PIP4K2C催化功能，同时减少非催化功能，如PIP4K2A、PIP4K2B和/或PIP4K2C蛋白与其它细胞蛋白和结构之间的支架作用。
可以通过各种方式，对PIP4K2A、PIP4K2B和/或PIP4K2C蛋白进行直接破碎、降解或不稳定处理。
例如，PIP4K2A、PIP4K2B和/或PIP4K2C蛋白可以通过用向细胞发出信号以降解PIP4K2A、PIP4K2B和/或PIP4K2C蛋白的药剂标记内源性PIP4K2A、PIP4K2B和/或PIP4K2C蛋白的方式进行降解。
例如，有一种药剂，即E3泛素连接酶，它可以向细胞发出信号以降解PIP4K2A、PIP4K2B和/或PIP4K2C蛋白。结合部分可以用于将降解信号(例如，E3泛素连接酶)与PIP4K2A、PIP4K2B和/或PIP4K2C蛋白连接。此类结合部分可以是特异性结合PIP4K2A、PIP4K2B和/或PIP4K2C的抗体、肽、多糖、脂质或小分子。抗体结合型PIP4K2A、PIP4K2B和/或PIP4K2C蛋白可以由胞质抗体受体TRIM21识别，所述TRIM21是以高亲和力与抗体Fc结构域结合的E3泛素连接酶。结合部分可与E3泛素连接酶连接，将E3泛素连接酶引导到一种或多种PIP4K2A、PIP4K2B和/或PIP4K2C蛋白。PIP4K2A、PIP4K2B和/或PIP4K2C蛋白的任何结合部分均可调整，使E3泛素连接酶与PIP4K2A、PIP4K2B和/或PIP4K2C蛋白直接或间接连接，或标记E3泛素连接酶。
结合PIP4K2A、PIP4K2B和/或PIP4K2C蛋白的小分子包含例如WO/2016/210291和WO/2016/210296所述的小分子。
PIP4K2A、PIP4K2B和/或PIP4K2C的降解或抑制方法可以包括将复合物引入受试者，其中，所述复合物为具有E3泛素连接酶活性的蛋白质，所述蛋白质与受试者的PIP4K2A、PIP4K2B和/或PIP4K2C蛋白的结合部分连接，或与受试者的细胞群连接。然后泛素化出现，PIP4K2A、PIP4K2B和/或PIP4K2C蛋白发生降解。
PIP4K2A、PIP4K2B和/或PIP4K2C的降解或抑制方法可以包括诱导E3泛素连接酶的表达，或将外源性E3泛素连接酶(例如，TRIM21)表达系统引入受试者或受试者的细胞群，并且将PIP4K2A、PIP4K2B和/或PIP4K2C蛋白的抗体引入受试者或受试者的细胞群。然后泛素化出现，随后抗体结合型PIP4K2A、PIP4K2B和/或PIP4K2C蛋白发生降解。
例如，至少四种E3连接酶(即，MDM2、IAP、VHL和小脑蛋白(cereblon)可以用作PIP4K2A、PIP4K2B和/或PIP4K2C蛋白降解标记。
小鼠双微体2同源物(MDM2)，也称为E3泛素-蛋白连接酶Mdm2，是人体内由MDM2基因编码的核定位蛋白。编码蛋白可以通过靶向p53等肿瘤抑制蛋白进行蛋白酶体降解，以促进肿瘤形成。Mdm2蛋白既用作识别p53肿瘤抑制因子的N端反式激活结构域(TAD)的E3泛素连接酶，又用作p53转录活化的抑制剂。
智人E3泛素蛋白连接酶Mdm2(异构体2)序列的一个实例可以作为登录号NP_001354919XP_005268929获得，并且在下文显示显示为SEQ ID NO:12。
智人E3泛素蛋白连接酶Mdm2的另一个实例可以作为登录号CAP16727.1获得，并且在下文显示为SEQ ID NO:13。
1 MCNTNMSVPT DGAVTTSQIP ASEQETLVRP KPLLLKLLKS
41 VGAQKDTYTM KEFATKHRAK NIPV
智人E3泛素蛋白连接酶Mdm2的另一个实例可以作为登录号CAP16726.1获得，并且在下文显示为SEQ ID NO:14。
1 MCNTNMSVPT DGAVTTSQIP ASEQETLVRP KPLLLKLLKS
41 VGAQKDTYTM KENHRTQVHL
智人E3泛素蛋白连接酶Mdm2的另一个实例可以作为登录号CAP16725.1获得，并且在下文显示为SEQ ID NO:15。
1 MCNTNMSVPT DGAVTTSQIP ASEQETLVRP KPLLLKLLKS
41 VGAQKDTYTM KEENIYHDLQ ELGSSQSAGR KFR
凋亡蛋白抑制剂(IAP)属于保护性泛素连接酶，所述保护性泛素连接酶抑制经典的促凋亡蛋白，它们不仅能调节胱天蛋白酶和细胞凋亡，而且还能调节炎性信号传导和免疫、铜内稳态、促有丝分裂的激酶信号传导、细胞增殖以及细胞侵袭和转移。IAP可以充当直接的胱天蛋白酶抑制剂，并且可以直接与CASP3和CASP7的活性位点袋结合，以阻断底物进入。IAP还可以通过使CASP9保持在单体非活性状态，使CASP9失活。IAP充当调节NF-κ-B信号传导的E3泛素-蛋白连接酶，并且针对其E3泛素-蛋白连接酶活性的靶蛋白包含：RIPK1、CASP3、CASP7、CASP8、CASP9、MAP3K2/MEKK2、DIABLO/SMAC、AIFM1、CCS和BIRC5/生存素。IAP通过使COMMD1泛素化并促进其蛋白酶体降解而在铜内稳态中发挥作用，并且还可以用作NEDD8缀合路径的E3泛素-蛋白连接酶发挥作用，从而靶向效应胱天蛋白酶进行类泛素化(neddylation)和失活。IAP调节BMP信号传导路径以及SMAD和MAP3K7/TAK1依赖性路径，从而导致NF-κ-B和JNK活化。
智人IAP E3泛素-蛋白连接酶的序列的一个实例可从NCBI数据库作为登录号P98170.2获得，并且在下文中作为SEQ ID NO:16提供。
智人IAP E3泛素蛋白连接酶的另一个实例可以作为登录号Q13490.2获得，并且在下文显示为SEQ ID NO:17。
智人IAP E3泛素蛋白连接酶的另一个实例可以作为登录号Q96CA5.2获得，并且在下文显示为SEQ ID NO:18。
希佩尔-林道(von Hippel-Lindau，VHL)肿瘤抑制因子包含底物识别亚基/E3连接酶复合物VCB，其包含延伸蛋白(elongin)B和C以及包含Cullin-2和Rbx1的复合物。VHL的主要底物是缺氧诱导因子1α(HIF-1α)，即一种响应于低氧水平而上调促血管产生生长因子VEGF、红细胞诱导性细胞因子促红细胞产生素等基因的转录因子。
智人VHL E3泛素-蛋白连接酶的序列的一个实例可从NCBI数据库中作为登录号NP_000542.1获得，并且在下文中作为SEQ ID NO:19提供。
智人VHL E3泛素蛋白连接酶的另一个实例可以作为登录号NP_937799.1获得，并且在下文显示为SEQ ID NO:20。
智人VHL E3泛素蛋白连接酶的另一个实例可以作为登录号NP_001341652.1获得，并且在下文显示为SEQ ID NO:21。
小脑蛋白是一种人体内由CRBN基因编码的蛋白质。小脑蛋白与Lon蛋白酶蛋白家族有关。在哺乳动物的细胞质中发现，小脑蛋白与钙通道膜蛋白一起定位，并且认为小脑蛋白在脑发育中起到一定作用。小脑蛋白与受损DNA结合蛋白1(DDB1)、Cullin-4A(CUL4A)和cullin 1调节剂(ROC1)形成了E3泛素连接酶复合物。此复合物使许多其它蛋白质泛素化。通过尚未完全阐明的机制，靶蛋白的小脑蛋白泛素化使成纤维细胞生长因子8(FGF8)和成纤维细胞生长因子10(FGF10)水平升高。FGF8反过来能够调节许多发育过程，如肢体和听觉囊泡的形成。最终结果是，此泛素连接酶复合物对于胚胎中的肢体生长具有重要作用。在不存在小脑蛋白的情况下，DDB1与DDB2形成复合物，充当DNA损伤结合型蛋白。
智人小脑蛋白E3泛素-蛋白连接酶的序列的一个实例可从NCBI数据库作为登录号NP_057386.2获得，并且在下文中作为SEQ ID NO:22提供。
智人小脑蛋白E3泛素蛋白连接酶的另一个实例可以作为登录号NP_001166953.1获得，并且在下文显示为SEQ ID NO:23。
智人小脑蛋白E3泛素蛋白连接酶的另一个实例可以作为登录号XP_005265259.1获得，并且在下文显示为SEQ ID NO:24。
智人小脑蛋白E3泛素蛋白连接酶的另一个实例可以作为登录号XP_011532093.1获得，并且在下文显示为SEQ ID NO:25。
如上文所述，抗体结合型PIP4K2A、PIP4K2B和/或PIP4K2C蛋白可以由胞质抗体受体TRIM21所识别，所述TRIM21是以高亲和力与抗体的Fc结构域结合的E3泛素连接酶。在施用或诱导TRIM21表达的同时或在此之前，用与PIP4K2A、PIP4K2B和/或PIP4K2C蛋白特异性结合的抗体进行处理，可导致PIP4K2A、PIP4K2B和/或PIP4K2C蛋白发生降解。
智人E3泛素-蛋白连接酶TRIM21多肽序列的序列的一个实例可从NCBI数据库作为登录号NP_003132.2获得，并且在下文中作为SEQ ID NO:26提供。
类似地，蛋白质水解-靶向型嵌合体(PROTAC)系统可以用于标记PIP4K2A、PIP4K2B和/或PIP4K2C中的一种或多种，以进行选择性降解。PROTAC系统包含靶PIP4K2A、PIP4K2B和/或PIP4K2C蛋白的配体、E3泛素连接酶的配体和连接两个配体的接头。例如，参见Bondeson和Crew，《药理学和毒理学年评(Ann Rev Pharmacol Toxicol)》.57:107-123(2017)。
还可以使用能够诱导泛素化的E3泛素连接酶的片段。例如，E3泛素连接酶包含与E3泛素连接酶具有至少20个、至少22个、至少25个、至少27个、至少30个、至少35个、至少40个、至少50个相同的氨基酸的泛素连接酶。相同的氨基酸可以分布在整个E3泛素连接酶中，各氨基酸之间无需具有连续性，而是存在于同源位置中。
与本文所述的E3泛素连接酶中的任何E3泛素连接酶具有至少70％、80％、90％、95％、96％、97％、98％、99％或99％以上的序列一致性，或者与具有至少20个、至少22个、至少25个、至少27个、至少30个、至少35个、至少40个、至少50个氨基酸的E3泛素连接酶的片段具有至少70％、80％、90％、95％、96％、97％、98％、99％或99％以上的序列一致性。
在一些情况下，包含编码这些E3泛素连接酶蛋白中的任何E3泛素连接酶蛋白的核酸区段的表达载体可用于增加E3泛素连接酶蛋白的表达。
结合PIP4K的抗体
在一些情况下，在本文所述的组合物和方法中，可以使用与PIP4K特异性结合的分离抗体。此类抗体可以是单克隆抗体。在一些情况下，抗体可以是多克隆抗体。此类抗体还可以是人源化抗体或完全人抗体。抗体可以表现出一种或多种期望的功能性质，例如与PIP4K的高亲和力或特异性结合。
本文所述的方法和组合物可以包含PIP4K抗体，或PIP4K抗体与诱导或介导PIP4K2A、PIP4K2B和/或PIP4K2C降解的药剂的组合。
本文所提及的术语“抗体”包含整个抗体和任何抗原结合片段(即，“抗原结合部分”)或其单链。“抗体”是指包括通过二硫键相互连接的至少两个重(H)链和两个轻(L)链的糖蛋白或其抗原结合部分。每个重链包含重链可变区(本文中缩写为VH)和重链恒定区。重链恒定区包含三个结构域CH1、CH2和CH3。每个轻链包含轻链可变区(本文中缩写为VL)和轻链恒定区。轻链恒定区包含一个结构域CL。VH区和VL区可以进一步细分成高变区，称为互补决定区(CDR)，所述超变区散布有更保守的区，称为构架区(FR)。每个VH和VL由按以下顺序从氨基端到羧基端布置的三个CDR和四个FR构成：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合，包含免疫系统的各种细胞(例如，效应细胞)以及经典补体系统的第一组分(C1q)。
本文中使用的本文中使用的术语抗体的“抗原结合部分”(或简称为“抗体部分”)是指保留与抗原(例如PIP4K的表位或结构域)特异性结合能力的一个或多个抗体片段。研究已经表明，抗体的抗原结合功能可以由全长抗体的片段执行。术语抗体的“抗原结合部分”内涵盖的结合片段实例包含(i)Fab片段，即由VL、VH、CL和CH1结构域组成的单价片段；(ii)F(ab')2片段，即包括在铰链区由二硫键连接的两个Fab片段的二价片段；(iii)由VH和CH1结构域组成的Fd片段；(iv)由抗体单臂的VL和VH结构域组成的Fv片段；(v)由VH结构域组成的dAb片段(Ward等人，(1989)《自然》341:544-546)；以及(vi)分离的互补决定区(CDR)。此外，尽管Fv片段的两个结构域VL和VH由单独基因进行编码，但是可以使用重组方法，通过使所述两个结构域制备成单个蛋白质链的合成接头来连接所述两个结构域，其中，VL和VH区配对，形成单价分子(称为单链Fv(scFv)；参见例如Bird等人(1988)《科学(Science)》242:423-426；和Huston等人(1988)《美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)》85:5879-5883)。此类单链抗体还旨在纳入到术语抗体的“抗原结合部分”中。利用本领域技术人员已知的常规技术，可以获得这些抗体片段，并以与完整抗体相同的方式筛选片段，以实现实用性。
本文中使用的本文中使用的“分离抗体”指基本上不含具有不同抗原特异性的其它抗体的抗体(例如，特异性结合PIP4K的分离抗体基本上不含特异性结合PIP4K以外抗原的抗体)。然而，在一些情况下，抗体ay与PIP4K蛋白变体或来自其它物种的PIP4K等其它抗原具有交叉反应性。此外，分离抗体可以基本上不含其它细胞材料和/或化学物质。
本文中使用的术语“单克隆抗体”或“单克隆抗体组合物”是指单分子组合物的抗体分子的制剂。单克隆抗体组合物对特定表位显示出单一结合特异性和亲和力。
本文中使用的术语“人抗体”旨在包含具有可变区的抗体，在所述可变区中，构架区和CDR区均来源于人种系免疫球蛋白序列。此外，如果抗体含有恒定区，则恒定区也来源于人种系免疫球蛋白序列。本发明的人抗体可以包含非人种系免疫球蛋白序列编码的氨基酸残基(例如，由体外随机或位点特异性引入的突变，或者由体内体细胞突变引入的突变)。然而，本文中使用的术语“人抗体”不包含来源于小鼠等另一种哺乳动物物种种系的CDR序列已经移植到人构架序列上的抗体。
术语“人单克隆抗体”是指显示出单一结合特异性的抗体，所述抗体具有可变区，在所述可变区中，构架区和CDR区均来源于人种系免疫球蛋白序列。在一个实施例中，人单克隆抗体由杂交瘤产生，所述杂交瘤包含从例如转基因小鼠的转基因非人动物中获得的B细胞，这种动物具有一个基因组，其中包括与永生化细胞融合的人重链转基因和轻链转基因。
本文中使用的术语“重组人抗体”包含所有通过重组防止制备、表达、产生或分离的人抗体，例如(a)从对人免疫球蛋白基因具有转基因性或转染色体性的动物(例如，小鼠)或由其制备的杂交瘤中分离的抗体(下文予以进一步描述)；(b)从经转化可表达人抗体的宿主细胞中分离的抗体，例如从转染瘤中分离的抗体；(c)从重组的组合人抗体库中分离的抗体；以及(d)通过涉及将人免疫球蛋白基因序列剪接成其它DNA序列的任何其它方式制备、表达、产生或分离的抗体。此类重组人抗体具有可变区，在所述可变区中，构架区和CDR区来源于人种系免疫球蛋白序列。然而，在某些实施例中，此类重组人抗体可以经历体外诱变(或者当使用转基因人Ig序列的动物时，经历体内体细胞诱变)，因此，重组抗体的VL区和VH区的氨基酸序列是指，虽然来源于人种系VL和VH序列并与这些序列相关，但可能并非天然体内存在于人抗体种系组库内的序列。
本文中使用的“异构体”是指由重链恒定区基因编码的抗体类别(例如，IgM或IgG1)。
短语“识别抗原的抗体”和“对抗原特异的抗体”在本文中与术语“与抗原特异性结合的抗体”可以互换使用。
术语“人抗体衍生物”是指人抗体的任何修饰形式，例如抗体和另一种药剂或抗体的缀合物。
术语“人源化抗体”指来源于小鼠等另一种哺乳动物物种的种系的CDR序列已经移植到人构架序列上的抗体。在人构架序列内，可以进行额外构架区修饰。
术语“嵌合抗体”指可变区序列来源于一个物种并且恒定区序列来源于另一种物种的抗体，例如可变区序列来源于小鼠抗体并且恒定区序列来源于人抗体的抗体。
本文中使用的“与PIP4K特异性结合”的抗体指KD为1×10-7M或更小，更优选地5×10-8M或更小，更优选地1×10-8M或更小，更优选地5×10-9M或更小，甚至更优选地介于1×10-8M与1×10-10M之间或更小，并且与特定类型PIP4K结合的抗体。
本文中使用的术语“Kassoc”或“Ka”指特定抗体-抗原相互作用的缔合速率，而本文中使用的术语“Kdis”或“Kd”指特定抗体-抗原相互作用的解离速率。本文中使用的术语“KD”指解离常数，所述解离常数从Kd与Ka之比(即，Kd/Ka)获得，并表示为摩尔浓度(M)。可以使用本领域既定方法确定抗体的KD值。用于确定抗体KD的优选方法是利用表面等离子体共振，优选使用BiacoreTM系统等生物传感器系统。
本发明的抗体的特征在于抗体的特定功能特征或性质。例如，抗体与人PIP4K特异性结合。优选地，本发明的抗体以高亲和力与PIP4K结合，例如，KD为1×10-7M或以下(例如，小于1×10-8M或小于1×10-9M)。抗体可以表现出以下特性中的一个或多个特性：
(a)以1×10-7M或更小的KD与一种或多种PIP4K结合；
(b)促进一种或多种类型PIP4K蛋白的降解；
(c)增强胰岛素信号传导或减少胰岛素抵抗；
(d)减轻糖尿病的症状或严重程度；
(e)增强免疫应答；
(f)减少癌细胞生长或癌症进展；或
(g)其组合。
可以利用测定手段，评估抗体对PIP4K的结合能力，例如包括ELISA、蛋白质印迹和RIA。还可以通过本领域中已知的BiacoreTM分析等标准测定，评估抗体的结合动力学特征(例如，结合亲和力)。
鉴于主题抗体制剂可以与PIP4K结合，VL和VH序列可以“混合和匹配”以产生与PIP4K结合的其它结合分子。可以利用结合测定(例如，ELISA)，检测此类“混合和匹配”抗体的结合性质。当VL和VH链混合和匹配时，来自特定VH/VL配对的VH序列可由结构上类似的VH序列所替代。同样，优选地，来自特定VH/VL配对的VL序列可由结构上类似的VL序列所替代。
因此，在一方面，本发明提供了一种分离的单克隆抗体或其抗原结合部分，包括：
(a)一个重链可变区，包括氨基酸序列；以及
(b)一个轻链可变区，包括氨基酸序列；
其中，所述抗体特异性结合PIP4K。
在一些情况下，独立于CDR1和/或CDR2结构域的CDR3结构域可以单独确定抗体对同源抗原的结合特异性，并且可基于常见CDR3序列可预测地生成具有相同结合特异性的多个抗体。例如，参见Klimka等人，《英国癌症杂志(British J.of Cancer)》83(2):252-260(2000)(其中描述了仅使用鼠抗CD30抗体Ki-4的重链可变结构域CDR3，即可产生人源化抗CD30抗体)；Beiboer等人，《分子生物学杂志(J.Mol.Biol.)》296:833-849(2000)(其中描述了仅使用亲本鼠MOC-31抗EGP-2抗体的重链CDR3序列的重组上皮糖蛋白-2(EGP-2)抗体)；Rader等人，《美国国家科学院院刊》95:8910-8915(1998)(其中描述了使用重链和轻链可变CDR3结构域的人源化抗整合素αvβ3抗体组)。因此，在一些情况下，混合和匹配的抗体或人源化抗体含有对PIP4K具有特异性的CDR3抗原结合结构域。
抑制PIP4K的核酸
在本文所述的组合物和方法中，可以使用各种具有PIP4K功能的抑制剂。例如，其中一种类型的PIP4K抑制剂可以是抑制性核酸。例如，通过使用与编码PIP4K的内源性(靶)核酸特异性结合的抑制性核酸，可以抑制内源性PIP4K的表达或翻译。
在细胞内或严格条件下，抑制性核酸可以具有与PIP4K核酸杂交的至少一个区段。抑制性核酸可以减少编码PIP4K的核酸的表达。抑制性核酸可与基因组DNA、信使RNA或其组合杂交。抑制性核酸可以结合到质粒载体或病毒DNA中。所述抑制性核酸可以是单链或双链、环状或线性核酸。
抑制性核酸是长度超过13个核苷酸的核糖核苷酸或脱氧核糖核苷酸的聚合物。抑制性核酸可以包含天然存在的核苷酸；硫代磷酸酯等合成、修饰或假核苷酸；以及具有P32、生物素或地高辛(digoxigenin)等可检测标签的核苷酸。抑制性核酸可以降低PIP4K核酸的表达和/或活性。此类抑制性核酸可与PIP4K核酸的区段(例如，与PIP4K mRNA)完全互补。可替代地，相对于PIP4K序列，在抑制性核酸序列中允许存在某种可变性。例如，PIP4K核酸或PIP4K蛋白可与靶PIP4K核酸具有至少85％的序列一致性和/或互补性，或至少90％的序列一致性和/或互补性，或至少95％的序列一致性和/或互补性，或至少96％的序列一致性和/或互补性，或至少97％的序列一致性和/或互补性，或至少98％的序列一致性和/或互补性，或至少99％的序列一致性和/或互补性。
在细胞内条件下或严格杂交条件下，抑制性核酸可与PIP4K核酸杂交，并足以抑制PIP4K核酸的表达。细胞内条件是指通常存在于例如动物或哺乳动物细胞的细胞内部的温度、pH和盐浓度等条件。此类动物或哺乳动物细胞的一个实例是肌肉、肝、脂肪或如胰岛朗格汉斯细胞(Langerhans cell)、胰腺祖细胞或胰腺β细胞等胰腺细胞。然而，由于胰岛素抵抗通常在肌肉、脂肪和肝细胞对胰岛素应答不良并且无法轻易摄取葡萄糖的情况下发生，所以细胞靶标可以是非胰腺细胞(例如，肌肉、肝、脂肪、神经、淋巴细胞等)。通常，严格杂交条件可选择为在限定的离子强度和pH下比具体序列的热熔点(Tm)低约5℃。然而，严格条件涵盖比所选序列的热熔点低约1℃到约20℃范围内的温度，这取决于本文以其它方式进行量化的所需严格程度。例如，包括与PIP4K编码或侧翼序列精确互补的2个、3个、4个或5个或更多个连续核苷酸段的抑制性寡核苷酸可以各自由与邻近编码序列不互补的连续核苷酸段分离，并且此类抑制性核酸仍然可以抑制PIP4K核酸的功能。通常，每段连续核苷酸的长度为至少4个、5个、6个、7个或8个或更多个核苷酸。非互补中间序列的长度可以是1个、2个、3个或4个核苷酸。
本领域技术人员使用计算出的与有义核酸杂交的抑制性核酸的熔点，即可估计抑制特定靶核酸表达的容许失配程度。例如，本发明的抑制性核酸包含短发夹RNA、小干扰RNA、核酶或反义核酸分子。
抑制性核酸分子可以是单链或双链核酸分子(例如小干扰RNA(siRNA)，并且可以以酶依赖的方式或通过空间阻断起作用。以酶依赖性方式起作用的抑制性核酸分子包含依靠RNase H活性来降解靶mRNA的形式。这些抑制性核酸分子包含单链DNA、RNA和硫代磷酸酯分子，以及双链RNAi/siRNA系统，所述系统涉及通过有义-反义链配对进行靶mRNA识别，之后通过RNA诱导的沉默复合物降解靶mRNA。不依赖于RNase-H空间阻断的抑制性核酸通过与靶mRNA结合并妨碍其它过程来干扰基因表达或其它mRNA依赖性细胞过程。空间阻断的抑制性核酸包含2'-O烷基(通常在包含RNase-H依赖性反义寡核苷酸的嵌合体中)、肽核酸(PNA)、锁核酸(LNA)和吗啉反义寡核苷酸。
例如，小干扰RNA可以用于特异性减少PIP4K翻译，以便减少编码多肽的翻译。SiRNA以序列特异性方式介导转录后基因沉默。参见例如网站invitrogen.com/site/us/en/home/Products-and-Services/Applications/rnai.html。一旦结合到RNA诱导的沉默复合物中，siRNA通过将复合物导向同源mRNA转录物来介导同源内源性mRNA转录物的切割，然后由复合物切割所述转录物。siRNA可以与PIP4K mRNA转录物的任何区同源。同源区的长度可以是30个核苷酸或更少，如长度小于25个核苷酸，或例如约21个到23个核苷酸。SiRNA通常是双链的，并且可以具有两个核苷酸的3'突出端，例如3'突出UU二核苷酸。可以采用siRNA的设计方法，参见例如Elbashir等人《自然》411:494-498(2001)；Harborth等人《反义核酸药物开发(Antisense Nucleic Acid Drug Dev.)》13:83-106(2003)。
用于表达发夹siRNA的pSuppressorNeo载体可从IMGENEX公司(加利福尼亚圣地亚哥(San Diego，California)购买，用于制备抑制PIP4K表达的siRNA或shRNA。siRNA或shRNA表达质粒的构建涉及对mRNA靶标区的选择，这可能是一个反复试错的过程。然而，Elbashir等人已经提供了一些指南，并且这些指南似乎在约80％的时间内都能起作用。Elbashir，S.M.等人《使用小干扰RNA分析哺乳动物体细胞中的基因功能(Analysis of genefunction in somatic mammalian cells using small interfering RNAs)》。《方法(Methods)》，2002.26(2):第199-213页。因此，对于合成siRNA或shRNA的合成，可以优选选择起始密码子下游50个到100个核苷酸处的靶标区。应该避免5'和3'非翻译区以及靠近起始密码子的区，因为这些区可能含有更丰富的调节蛋白结合位点。由于siRNA可以从AA开始，因此有义和反义siRNA链均具有3'UU突出，并且G/C含量约为50％。合成siRNA或shRNA的序列实例是5'-AA(N19)UU，其中，N为mRNA序列中的任何核苷酸，并且G-C含量约为50％。可以将所选序列与人类基因组数据库中的其它序列进行比较，以最大限度地减少与其它已知编码序列的同源性(例如通过Blast搜索，例如通过NCBI网站)。
SiRNA可以是化学合成、通过体外转录产生或从siRNA表达载体或PCR表达盒表达。参见例如网站invitrogen.com/site/us/en/home/Products-and-Services/Applications/rnai.html。当siRNA从表达载体或PCR表达盒表达时，编码siRNA的插入物可以表达为折叠成siRNA发夹或shRNA的RNA转录物。因此，RNA转录物可以包含有义siRNA序列，所述有义siRNA序列通过形成发夹环的间隔子序列以及3'端处的U串与其反向互补反义siRNA序列连接。发夹环可以具有任何适当的长度，例如长度为3个到30个核苷酸，或长度为约3个到23个核苷酸，并且可以包含各种核苷酸序列，例如包含AUG、CCC、UUCG、CCACC、CTCGAG、AAGCUU和CCACACC。还可以通过切割直接或通过转基因或病毒引入的双链RNA，在体内产生siRNA。在一些生物体中，可能会发生RNA依赖性RNA聚合酶的扩增。
使用通过从包含抑制性核酸序列的表达载体或表达盒表达等方法，可以制备短发夹RNA、siRNA或反义寡核苷酸等抑制性核酸。可替代地，所述抑制性核酸可以通过化学合成使用天然存在的核苷酸、经修饰的核苷酸或其任何组合制备。在一些实施例中，抑制性核酸由经修饰的核苷酸或非磷酸二酯键制成，例如，所述核苷酸或非磷酸二酯键的设计可以增加抑制性核酸的生物稳定性，或增加抑制性核酸与靶PIP4K核酸之间形成的双链体的细胞内稳定性。
基因组修饰以减少PIP4K
在一些情况下，通过一个或多个PIP4K基因的基因组修饰，即可减少PIP4K的功能性表达。
将修饰引入细胞的基因组的方法的非限制性实例可以包括使用显微注射、病毒递送、重组酶技术、同源重组、TALENS、CRISPR和/或ZFN，参见例如Clark和Whitelaw《自然评论：遗传学(Nature Reviews Genetics.)》4:825-833(2003)；所述文献通过本发明的整体引用，成为本发明的一部分。
例如，锌指核酸酶(ZFN)、转录激活子样效应核酸酶(TALEN)和/或大范围核酸酶等核酸酶可与允许核酸酶靶向基因组PIP4K位点的向导核酸配合使用。在一些情况下，靶向载体可以用于引入一个或多个基因组PIP4K位点的缺失或修饰。
“靶向载体”是指通常具有与所关注基因的区段同源的5'侧翼区和3'侧翼区的载体。5'侧翼区和3'侧翼区可以围绕包括待插入基因中的修饰和/或外来DNA序列的DNA序列。例如，外来DNA序列可以编码可选择标志物。在一些情况下，靶向载体不包括可选择标志物，但此类可选择标志物可以有助于对具有所需突变的细胞进行鉴定和选择。合适的可选择标志物的实例包括氯霉素(chloramphenicol)抵抗、庆大霉素(gentamycin)抵抗、卡那霉素(kanamycin)抵抗、大观霉素(spectinomycin)抵抗(SpecR)、新霉素(neomycin)抵抗基因(NEO)等抗生素抵抗基因和/或潮霉素β-磷酸转移酶基因(hygromycinβ-phosphotransferase gene)。5'侧翼区和3'侧翼区可以与基因内的区同源，或与待缺失、修饰或由不相关的DNA序列所替代的基因侧翼的区同源。
在有利于同源重组的条件下，靶向载体在体内(例如，在细胞内)与所关注的天然基因接触。例如，在用靶向载体转化蓝藻细胞的条件下，细胞可以与靶向载体接触。
典型的靶向载体含有核酸片段，核酸片段与基因座5'端和3'端的距离不小于约0.1kb且不大于约10.0kb，该基因座对待修饰基因进行编码(例如基因组PIP4K位点)。这两个片段中间隔着核酸的中间片段，该核酸中间片段对待引入的修饰进行编码。当所得构建体在此基因座部位与染色体同源重组时，会导致修饰的引入，例如，一部分基因组PIP4K位点的缺失、基因组PIP4K启动子或编码区位点的替代或非保守密码子或终止密码子的插入。
在一些情况下，Cas9/CRISPR系统可以用于产生基因组PIP4K的修饰，减少PIP4K基因产物的表达或功能。成簇规则间隔的短回文重复序列(CRISPR)/CRISPR相关(Cas)系统可用于例如RNA可编程基因组编辑(参见例如Marraffini和Sontheimer《自然评论：遗传学》11:181-190(2010)；Sorek等人《自然评论：微生物学(Nature Reviews Microbiology)》2008 6:181-6；Karginov和Hannon《分子细胞》2010 1:7-19；Hale等人《分子细胞》2010:45:292-302；Jinek等人《科学》2012 337:815-820；Bikard和Marraffini《当前免疫学观点(Curr Opin Immunol)》2012 24:15-20；Bikard等人《细胞宿主和微生物(Cell Host&Microbe)》2012 12:177-186；上述所有文献通过本发明的整体引用，成为本发明的一部分)。可以使用CRISPR向导RNA，将Cas酶靶向基因组中的期望位置，在所述期望位置处产生双链断裂。例如，这项技术在Mali等人《科学》2013 339:823-6中予以说明；所述文献通过本发明的整体引用，成为本发明的一部分。用于CRISPR介导的基因组编辑的设计和用途的试剂盒可商购获得，例如加利福尼亚州山景城的系统生物科学公司(System Biosciences，Mountain View，CA)生产的PRECISION X CAS9 SMART NUCLEASETM系统(目录号CAS900A-1)。
在其它情况下，可以使用噬菌体P1的cre-lox重组系统(由Abremski等人在1983年《细胞》32:1301(1983)、Sternberg等人《冷泉港定量生物学研讨会》第XLV卷297(1981)中予以说明)和其它重组系统可以用于促进基因组PIP4K位点的重组和改变。cre-lox系统利用从噬菌体P1中分离的cre重组酶结合重组酶所识别的DNA序列(称为lox位点)。此重组系统对于在植物细胞(参见例如第5658772号美国专利)、动物细胞(第4959317号美国专利和第5801030号美国专利)以及在病毒载体中(Hardy等人，《病毒学杂志(J.Virology》71:1842(1997)中实现重组有效。
如此结合的基因组突变可以改变编码的PIP4K基因产物中的一个或多个氨基酸。例如，对基因组位点进行修饰，使编码PIP4K蛋白更易降解，或者稳定性更差，缩短此类蛋白质的半衰期。在另一个实例中，可以修饰基因组位点，使PIP4K多肽的至少一个氨基酸缺失或突变，以降低至少一种类型PIP4K的酶活性。在一些情况下，对PIP4K多肽的保守氨基酸或保守结构域进行修饰。例如，PIP4K多肽保守结构域中的一个保守氨基酸或若干氨基酸可以由具有不同于保守氨基酸的物理和/或化学性质的一个或多个氨基酸所替代。例如，为了改变保守氨基酸的物理和/或化学性质，保守氨基酸可以缺失或由另一类别的氨基酸所替代，其中所述类别在下表6中进行鉴定。
表6
| 分类 | 基因编码的 |
| 疏水的 | A、G、F、I、L、M、P、V、W |
| 芳香族的 | F、Y、W |
| 非极性的 | M、G、P |
| 脂肪族的 | A、V、L、I |
| 亲水的 | C、D、E、H、K、N、Q、R、S、T、Y |
| 酸性的 | D、E |
| 碱性的 | H、K、R |
| 极性的 | Q、N、S、T、Y |
| 半胱氨酸样 | C |
PIP4K多肽可采用不同类型的氨基酸。实例见表7。
表7
与未经修饰的PIP4K基因产物表达或功能相比，此类基因组修饰可以使PIP4K基因产物的表达或功能降低至少10％、或至少15％、或至少20％、或至少25％、或至少30％、或至少35％、或至少40％、或至少45％、或至少50％。
胰岛素抵抗
如本文所述，PIP4K，具体地PIP4K2B蛋白的耗尽或降解可用于治疗胰岛素抵抗。
胰岛素刺激磷脂酰肌醇-4,5-二磷酸酯(PI(4,5)P2)转化为磷脂酰肌醇-3,4,5-三磷酸酯(PI(3,4,5)P3)，从而介导下游细胞应答。PI(4,5)P2由磷脂酰肌醇-4-磷酸5-激酶(PIP5K)和磷脂酰肌醇-5-磷酸4-激酶(PIP4K)产生。如本文所示，体外PIP4K(PIP4K2A、PIP4K2B和PIP4K2C)的丢失导致PI(4,5)P2的反常增加，以及伴随的胰岛素刺激的PI(3,4,5)P3产生的增加。令人惊讶的是，PIP4K的野生型或激酶死亡的突变体的重新引入恢复了细胞PI(4,5)P2水平和PI3K路径的胰岛素刺激，这表明PIP4K在调节PI(4,5)P2水平中的非催化依赖性作用。这些影响可解释为PIP4K缺失后PIP5K活性增加，所述PIP4K通常通过由PIP4KN端基序VMLXPDD(SEQ ID NO:5，其中X为任何氨基酸)介导的直接结合相互作用来抑制PIP5K活性。本文所述的实验表明，PIP4K在抑制PIP5K介导的PI(4,5)P2合成和胰岛素依赖性转化为PI(3,4,5)P3方面具有变构功能。本文所述的耗尽PIP4K酶的方法和组合物可用于增强胰岛素信号传导。
可增强或治疗胰岛素信号传导的药剂的鉴定方法
本发明进一步提供了可用于产生或鉴定用于预防和治疗糖尿病的治疗剂、增强胰岛素信号传导、降低胰岛素抵抗的筛选试验，以及用于产生或鉴定抑制PIP4K的药剂的测定。具体地，()()增强胰岛素信号传导、降低胰岛素抵抗、调节PIP5K介导的PI(4,5)P2合成、增加PIP5K活性以及提高胰岛素依赖性转化为PI(3,4,5)P3，在用于鉴定这些要素的各种测定中可使用PIP4K。
例如，在一个实施例中，本发明涉及一种鉴定可以抑制PIP4K的治疗剂的方法。此类方法可以是体外或体内方法。
所述方法可以涉及使用糖尿病或胰岛素信号传导的动物模型。例如，鉴定治疗剂的方法可以涉及将测试药剂施用于在肌肉、肝、脂肪、神经或胰腺细胞中表达PIP4K的实验动物，并且观察在实验动物中糖尿病、胰岛素抵抗或胰岛素信号传导的一种或多种症状是否得到改善。细胞可以包含肌肉细胞、肝细胞、淋巴细胞、脂肪细胞、神经细胞或其组合。在一些实施例中，所述方法还包括相较于尚未施用测试药剂的对照实验动物或也已经施用测试药剂但不表达PIP4K的对照实验动物，比较Akt、磷酸肌醇、PI(3,4,5)P3、PI(4,5)P2活性或水平。
可以采用的实验动物的实例包含小鼠、大鼠、狗、山羊、猴子和黑猩猩。通常，可以采用任何实验动物，只要其易患有糖尿病或对胰岛素不敏感。可以用作糖尿病模型的一种类型的小鼠品系是NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ(NSG)小鼠(例如，来自缅因州巴尔港的杰克逊实验室(Jackson Laboratory，Bar Harbor，ME)，所述小鼠腹膜内注射有链脲菌素(Streptozocin，STZ；例如，来自密苏里州圣路易斯的西格玛-奥德里奇公司(Sigma-Aldrich，St.Louis，MO)或是实例中所描述的其它小鼠品系。
通过使用此类方法，还可以确定已知和新鉴定治疗剂的剂量。例如，在一个实施例中，本发明包含一种鉴定可以抑制PIP4K和/或可以改善胰岛素信号传导的治试剂的剂量的方法。此种方法可以涉及向实验动物施用在体细胞(例如，肌肉、脂肪、肝、神经和其它细胞)中表达PIP4K的一系列测试剂量的治疗剂，并且观察在实验动物中哪种剂量抑制PIP4K和/或改善胰岛素信号传导。
本发明还提供了一种评估用于用PIP4K抑制剂或测试药剂治疗糖尿病的治疗有效剂量的方法，所述方法包含在体外确定药剂的LD100或ED50。此种方法允许计算用于改善胰岛素信号传导的每体积所需药剂的近似量。例如，通过培养细胞中的标准微量稀释方法，或通过向实验动物施用各种量的PIP4K抑制剂或测试药剂，确定所述近似量。
可以成功抑制PIP4K活性的测试药剂和测试剂量，例如，抑制至少2％、5％、10％、20％、40％、50％、60％、70％、80％、90％、95％或95％以上。可以成功抑制PIP4K活性由此改善胰岛素信号传导的测试药剂和测试剂量，例如改善至少2％、5％、10％、20％、40％、50％、60％、70％、80％、90％、95％或95％以上。治疗有效剂量还是基本上无毒的剂量。
用于治疗癌症的方法
PIP4K2A、PIP4K2B和/或PIP4K2C蛋白的降解或耗尽可用于预防、治疗和/或诊断癌症。在一些情况下，PIP4K2C蛋白其在免疫细胞中的表达水平高于PIP4K2A和PIP4K2B蛋白在免疫细胞中的表达水平，因此PIP4K2C蛋白是靶向蛋白。PIP4K2A蛋白、PIP4K2B蛋白和/或特别是PIP4K2C蛋白的降解或耗尽可以增强针对癌症和肿瘤的免疫应答。因此，本发明的一方面是一种治疗或抑制动物(例如人)的转移性肿瘤的建立和/或生长的方法。此类方法涉及向动物施用降解或耗尽PIP4K2A、PIP4K2B和/或尤其是PIP4K2C的组合物，由此治疗或抑制动物中癌症的建立和/或生长。同时兼顾人类和兽医用途。
如本文所示，PIP4K在调节细胞内信号传导方面具有非催化依赖性作用。本文提供的数据表明，细胞中三种PIP4K的耗尽改变了超出PI(5)P的磷酸肌醇水平。细胞中PIP4K的敲减和敲除导致PI(4,5)P2出现惊人增加，并伴随PI(4)P的降低。在培养生长期间，PI(3,4,5)P3的基础水平通常低于基于HPLC测定中的检测限。然而，在具有敲除PIP4K突变的细胞中观察到PI(3,4,5)P3出现基础升高，这表明增加的PI(4,5)P2能够被PI3K利用。PI(4,5)P2占所有磷酸肌醇的约50％，但是大多数与细胞结构、迁移和粘附所需的细胞骨架蛋白和支架蛋白结合。虽然PI(4,5)P2高度丰富，但是通过PIP5K局部产生PI(4,5)P2提供了对通过PI3K和PLC路径的信号传导的时空控制。
本文描述了用于治疗癌症和抑制癌症进展的方法。治疗或抑制动物中癌症的进展和/或转移性肿瘤的建立的方法可以包括向受试者动物(例如，人)施用治疗有效量的降解或耗尽PIP4K2A蛋白、PIP4K2B蛋白，和/或特别是PIP4K2C蛋白的组合物。治疗或抑制动物中转移性肿瘤的形成和/或生长的方法还可以包括此类组合物与一种或多种其它抗癌药剂或化学治疗剂一起施用。
在一些实施例中，所述方法还可以包括用于确定动物是否患有癌症或是否需要治疗以抑制转移性肿瘤的发展的检测步骤。此类检测步骤可以包括任何可获得的癌症测定。
本文中使用的术语“动物”是指易患有或患有与蛋白酶表达相关的疾病例如癌症的动物，如温血动物。哺乳动物包含牛、水牛、绵羊、山羊、猪、马、狗、猫、大鼠、兔、小鼠和人。还包含其它牲畜、家养动物和圈养动物。术语“农场动物”包含鸡、火鸡、鱼和其它农场动物。哺乳动物和包含鸟类的其它动物可以通过本文所述和要求保护的方法和组合物进行治疗。在一些实施例中，动物是人。
本文中使用的术语“癌症”包含实体动物肿瘤以及血液恶性肿瘤。术语“肿瘤细胞”和“癌细胞”在本文中可互换使用。
“实体动物肿瘤”包含头颈癌、肺癌、间皮瘤、纵隔癌、食管癌、胃癌、胰腺癌、肝胆系统癌、小肠癌、结肠癌、结直肠癌、直肠癌、肛门癌、肾癌、尿道癌、膀胱癌、前列腺癌、尿道癌、阴茎癌、睾丸癌、妇科器官癌、卵巢癌、乳腺癌、内分泌系统癌、皮肤中枢神经系统癌；软组织和骨肉瘤；以及皮肤和眼内起源的黑色素瘤。另外，可以治疗处于任何进展阶段的转移性癌症，如微转移性肿瘤、巨转移性肿瘤(megametastatic tumor)和复发性癌症。
术语“血液恶性肿瘤”包含儿童白血病和淋巴瘤、霍奇金氏病(Hodgkin'sdisease)、淋巴细胞和皮肤起源的淋巴瘤、急性和慢性白血病、浆细胞肿瘤和与AIDS相关的癌症。
本发明的方法和组合物还可以用于治疗肾上腺皮质癌、宫颈癌、子宫内膜癌、食管癌、头颈癌、肝癌、胰腺癌、前列腺癌、胸腺癌、类癌瘤、慢性淋巴细胞白血病、尤文氏肉瘤(Ewing's sarcoma)、妊娠滋养细胞肿瘤、肝母细胞瘤、多发性骨髓瘤、非小细胞肺癌、视网膜母细胞瘤或卵巢中的肿瘤。可以治疗或检测处于任何进展阶段的癌症，如原发性、转移性和复发性癌症。关于多种类型癌症的信息可以从例如美国癌症协会(American CancerSociety)(www.cancer.org)或例如Wilson等人.(1991)《哈里森内科医学原理(Harrison'sPrinciples of Internal Medicine)》，第12版，麦格劳-希尔出版公司(McGraw-Hill)发现。
癌症治疗或治疗可以包含减少癌细胞生长、癌细胞迁移或减少至少一种转移性肿瘤的建立。治疗还包含缓和或减轻多于一种癌症症状，如咳嗽、气短、咯血、淋巴结肿大、肝肿大、恶心、黄疸、骨痛、骨折、头痛、癫痫、全身性疼痛和其组合。所述治疗可以治愈癌症，例如，所述治疗可以预防癌症、可以基本上消除肿瘤形成和生长和/或可以阻止或抑制转移性癌细胞的迁移。
针对各种癌症，可以使用本领域技术人员可获得的方法，评估抗癌活性。例如，可以通过鉴定致死剂量(LD100)或50％有效剂量(ED50)或抑制本发明的组合物或药剂的50％生长剂量(GI50)，确定抗癌活性。在一方面，抗癌活性是在通过检测癌细胞标志物的表达水平或癌细胞标志物在远离原发性肿瘤位点的位点处的表达水平测量时，或在使用可获得的用于检测转移的方法评估时，减少50％、60％、70％、80％、90％、95％、97％、98％、99％或100％的癌细胞生长或转移的药剂的量。
本文所述的用于治疗癌症的组合物可以包含额外治疗剂，如额外抗癌剂或化学治疗剂、维生素、止痛剂和抗微生物剂。
可用于本文所述的组合物和方法中的抗癌剂包含细胞毒素、光敏剂和化学治疗剂。这些药剂包括但不限于叶酸拮抗剂、嘧啶抗代谢物、嘌呤抗代谢物、5-氨基乙酰丙酸、烷化剂、铂抗肿瘤剂、蒽环霉素(anthracycline)、DNA插层剂、表鬼臼毒素(epipodophyllotoxin)、DNA拓扑异构酶、微管靶向剂、长春花生物碱、紫杉烷、埃坡霉素(epothilone)和天冬酰胺酶。更多信息可以查阅Bast等人的《癌症医学(CancerMedicine)》，第5版，可以电子书的形式免费获得(参见网站ncbi.nlm.nih.gov/books/NBK20812/)。
叶酸拮抗剂是用作抗肿瘤剂、抗菌剂、抗炎症剂和免疫抑制剂的细胞毒性药物。虽然已经开发了若干叶酸拮抗剂，并且其中一些正在临床试验中，但甲氨蝶呤(methotrexate，MTX)是历史最悠久、使用范围最广的抗叶酸剂。MTX是用于治疗急性成淋巴细胞性白血病、淋巴瘤、骨肉瘤、乳腺癌、绒膜癌和头颈癌患者的化疗方案中的必不可少的药物，也是治疗如类风湿性关节炎、银屑病和移植物抗宿主疾病等非恶性疾病患者的重要药剂。
嘧啶抗代谢物包含氟尿嘧啶(fluorouracil)、胞嘧啶阿拉伯糖苷(cytosinearabinoside)、5-氮杂胞苷和2',2'-二氟-2'-脱氧胞苷。嘌呤抗代谢物包含6-巯基嘌呤、硫鸟嘌呤、别嘌呤醇(4-羟基吡唑并-3,4-d-嘧啶)、脱氧柯福霉素(deoxycoformycin)(喷司他丁(pentostatin)、2-氟腺苷阿拉伯糖苷(氟达拉滨；9-β-d-呋喃阿拉伯糖基-2-氟腺嘌呤)和2-氯脱氧腺苷(Cl-dAdo，克拉屈滨(cladribine)。除了嘌呤和嘧啶类似物之外，还开发了抑制产生最终核酸前体的生物合成反应的其它药剂。这些药剂包括磷酸乙酰基-L-天门冬氨酸(phosphonacetyl-L-aspartic acid，PALA)、布喹那钠(brequinar)、阿西维辛(acivicin)和羟基脲。
烷化剂和铂抗肿瘤化合物能够与蛋白质中的硫和DNA中的氮等富电子原子(亲核试剂)形成强化学键。尽管这些化合物会与许多生物分子发生反应，但这两类药剂的主要细胞毒性作用似乎是抑制通过它们与DNA反应产生的DNA复制和细胞分裂。然而，由于这两类药剂之间存在化学差异，使它们在抗肿瘤和毒性效果方面存在显著差异。最常用的烷化剂是氮芥。尽管目前已经合成和测试了数以千计的氮芥，但常用于癌症疗法的氮芥只有五种。这些二氯甲基二乙胺(mechlorethamine)(最初的“氮芥”)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、美法仑(melphalan)和苯丁酸氮芥(chlorambucil)。与氮芥密切相关的是，在目前疗法中以噻替哌(thiotepa)、丝裂霉素C(mitomycin C)和亚丝醌(diaziquone，AZQ)为代表的氮丙啶(氮丙啶)。噻替派(三乙烯硫代磷酰胺)已经用于卵巢癌和乳腺癌的治疗以及脑膜癌病的鞘内疗法。烷基链烷磺酸盐白消安(busulfan)是最早的烷化剂之一。此化合物是目前使用的少数通过SN2反应明显地烷基化的药剂之一。合普素凡(hepsulfam)，在临床前研究中，具有更广泛的抗肿瘤活性的一种白消安的烷基氨基磺酸盐类似物已经在临床试验中进行了评估，但迄今为止并未证明具有优于白消安的优势。
光敏剂诱导对细胞和组织的细胞毒性作用。光敏化合物在暴露于光后，可能会有毒性，或可能释放如单线态氧或其它氧化自由基等有毒物质，所述有毒物质损坏包含细胞膜和细胞结构的细胞材料或生物分子，并且此类细胞或膜损坏最终会杀死细胞。可以使用一系列光敏剂，包含补骨脂素(psoralen)、卟啉(porphyrin)、氯、苯环上具有2个到4个磺酸盐基团的铝酞菁(例如，AlPcS2a或AlPcS4)和酞菁。此类药物在暴露于光下时会有毒性。例如，光敏剂可以是称为5-氨基乙酰丙酸的氨基酸，其转化为一种荧光光敏剂原卟啉(protoporphyrin)IX。5-氨基乙酰丙酸的结构如下所示。
据信，拓扑异构酶毒剂与DNA、拓扑异构酶或任一分子结合。如蒽环霉素和放线菌素D等许多拓扑异构酶毒剂是通过插入作用以高亲和力与DNA结合的相对平面的疏水性化合物，这涉及化合物在邻近碱基对之间的堆叠。蒽环霉素插入双链DNA中并且产生干扰DNA和RNA合成的结构变化。若干临床相关的蒽环霉素如下图所示。
非插入型拓扑异构酶靶向型药物包括依托泊苷(etoposide)和替尼泊苷(teniposide)等表鬼臼毒素。依托泊苷在美国获批准用于治疗睾丸癌和小细胞肺癌。磷酸依托泊苷比依托泊苷更具有水溶性，并且在体内迅速转化为依托泊苷。其它非插入型拓扑异构酶靶向型药物包括拓扑替康(topotecan)和伊立替康(irinotecan)。
独特类别的天然产物抗癌药物来源于植物。与来源于细菌和真菌来源的药剂不同，以长春花和秋水仙生物碱为代表的植物产物，以及如紫杉醇(paclitaxel)(紫杉酚(Taxol)和鬼臼毒素(podophyllotoxin)等其它植物源性产物不靶向DNA。相反，所述植物源性产物与完整的微管，即细胞的细胞骨架的整体组分相互作用，或与其亚基分子，即微管蛋白相互作用。靶向微管的临床有用的植物产物包含长春花生物碱，主要是长春花碱(vinblastine，VLB)、长春新碱(vincristine，VCR)、长春瑞滨(vinorelbine，诺维本(Navelbine)，VRLB)和较新的长春花生物碱，即长春氟宁(vinflunine，VFL；20',20'-二氟-3',4'-二氢长春瑞滨)以及两种紫杉烷，即紫杉醇和多西他赛(泰索帝(Taxotere)。
下面提供了紫杉醇的结构。
优选地，将紫杉醇部分通过C10和/或C2羟基部分与肽连接。
可以在本文所述的方法和组合物中使用的药物的实例包括但不限于阿地白介素(aldesleukin)、5-氨基乙酰丙酸、天冬酰胺酶、硫酸博来霉素(bleomycin sulfate)、喜树碱(camptothecin)、卡铂(carboplatin)、卡莫司汀(carmustine)、顺铂(cisplatin)、克拉屈滨、环磷酰胺(冻干的)、环磷酰胺(非冻干的)、阿糖胞苷(cytarabine)(冻干粉)、达卡巴嗪(dacarbazine)、放线菌素(dactinomycin)、柔红霉素(daunorubicin)、己烯雌酚(diethyistilbestrol)、多柔比星(doxorubicin)(多柔比星、4'-表柔比星、4-或4'-脱氧多柔比星)、依泊汀α(epoetin alfa)、埃斯波霉素(esperamycin)、依替膦酸钠(etidronate)、依托泊苷、N,N-双(2-氯乙基)-羟基苯胺、4-羟基环磷酰胺、非诺特罗(fenoterol)、非格司亭(filgrastim)、氟尿苷(floxuridine)、磷酸氟达拉滨(fludarabine phosphate)、氟胞嘧啶核苷(fluorocytidine)、氟尿嘧啶、氟代尿苷(fluorouridine)、戈舍瑞林(goserelin)、盐酸格拉司琼(granisetron hydrochloride)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、干扰素α-2a、干扰素α-2b、甲酰四氢叶酸钙(leucovorin calcium)、亮丙瑞林(leuprolide)、左旋咪唑(levamisole)、氮芥(mechlorethamine)、甲羟孕酮(medroxyprogesterone)、美法仑、甲氨蝶呤、丝裂霉素、米托蒽醌(mitoxantrone)、毒蕈碱(muscarine)、奥曲肽(octreotide)、盐酸昂丹司琼(ondansetron hydrochloride)、羟基保泰松(oxyphenbutazone)、紫杉醇、帕米膦酸盐(pamidronate)、培门冬酶(pegaspargase)、普卡霉素(plicamycin)、水杨酸(salicylic acid)、沙丁胺醇(salbutamol)、沙格司亭(sargramostim)、链脲菌素(streptozocin)、紫杉酚、特布他林(terbutaline)、特非那定(terfenadine)、噻替派、替尼泊苷、长春花碱、长春地辛(vindesine)和长春新碱。可以用于本文所述的方法和组合物的其它药物包括例如WO 98/13059；Payne，2003；US 2002/0147138和本领域技术人员可获得的其它参考文献中公开的药物。
组合物
PIP4K降解剂、PIP4K抑制剂、PIP4K突变剂和/或PIP4K结合(例如，抗体)剂可以调配成具有或不具有额外治疗剂的组合物，并且以适用于所选施用途径的各种形式施用于人类患者等动物。施用途径包括例如口服途径、局部途径、肠胃外途径、腹膜内途径、静脉内途径和动脉内途径。
组合物可以调配成药物剂型。此类药物剂型可以包含(a)液体溶液；(b)含有液体、固体、颗粒或明胶的片剂、小袋或胶囊；(c)呈适当液体形式的悬浮液；以及(d)合适的乳剂。
活性剂(PIP4K降解剂、PIP4K抗体、其它治疗剂)的溶液可以在水或盐水中制备，并且任选地与其它药剂混合。例如，用于静脉内或动脉内施用的调配物可以包含无菌水溶液，所述无菌水溶液还可以含有缓冲剂、稀释剂、稳定剂、无毒表面活性剂、螯合剂、聚合物和/或其它合适的添加剂。通过以无菌方式将所需量的活性剂与各种其它成分掺入适当的溶剂中，或在组装后进行灭菌(例如，过滤灭菌)，制备无菌可注射溶液。
在另一个实施例中，可以制备活性剂-脂质颗粒，并将其掺入广泛的含脂质剂型中。例如，含有活性剂-脂质颗粒的悬浮液可以以脂质体、凝胶、油、乳剂、局部乳膏、糊剂、软膏、洗剂、泡沫、摩丝的形式等调配和施用。
在一些实施例中，活性剂可以在脂质体组合物中调配。无菌水溶液、活性剂-脂质颗粒或包括活性剂的分散体适用于通过封装在脂质体中进行施用。此类脂质体调配物可以包含悬浮在水、盐水或PEG 400等稀释剂中的有效量的脂质体封装的活性剂。
脂质体可以是单层或多层，并选自以下几种成分形成：磷脂酰胆碱、二棕榈酰磷脂酰胆碱、胆固醇、磷脂酰乙醇胺、磷脂酰丝氨酸、脱豆蔻酰磷脂酰胆碱(demyristoylphosphatidylcholine)及其组合。多层脂质体包括多个隔室，这些隔室与单层囊泡组成类似，但制备后可以提供截留溶液或乳剂中的银组分。另外，脂质体调配物中可以包含聚乙二醇或其它材料等其它佐剂和改性剂。
虽然脂质体的合适调配物包含二棕榈酰-磷脂酰胆碱:胆固醇(1:1)，但本领域技术人员应当理解的是，任何数量的脂质体双层组合物均可用于本发明的组合物。脂质体可以通过以下公开的方法等各种已知方法制备：第4235871号美国专利和RRC，《脂质体：实用方法(Liposomes:A Practical Approach)牛津IRL出版社(IRL Press，Oxford)，1990，第33-101页。
含有活性剂的脂质体可以具有修饰，如将非聚合物分子与脂质体的外部结合，如赋予脂质体期望的酶促或表面识别特征的半抗原、酶、抗体或抗体片段、细胞因子和激素以及其它小蛋白质、多肽或非蛋白分子。优先将脂质体靶向具体器官或细胞类型的表面分子包含例如将脂质体靶向携带具体抗原的细胞的抗体。目前可以获得用于偶联此类分子的技术(参见例如第4762915号美国专利，所述美国专利的公开内容通过本发明的整体引用，成为本发明的一部分)。可替代地或结合地，本领域技术人员将会理解的是，可以使用任何数量的带有正或负净电荷的脂质，改变脂质体膜的表面电荷或表面电荷密度。脂质体还可以掺入有热敏感或pH敏感的脂质，作为脂质双层的组分，对脂质囊泡膜进行受控降解。
与活性剂配合使用的脂质体调配物还可以按照WO 2005/105152(其公开内容以其整体并入本文)中公开的方法进行调配。简而言之，此类调配物包括作为脂质组分的磷脂和类固醇。在不使用抗体或其它分子的情况下，这些调配物有助于将与其相关的分子靶向到体内位置。
称为免疫脂质体的抗体缀合的脂质体可用于在其水性隔室中携带活性剂。在抗体标记的脂质体(免疫脂质体)内提供的活性剂的组合物可以将活性剂特异性靶向到特定细胞或组织类型，以引发局部效应。用于制备此类免疫脂质体组合物的方法可查阅例如Selvam M.P.等人，1996《抗病毒研究(Antiviral Res)》12月；33(1):11-20(其公开内容通过本发明的整体引用，成为本发明的一部分)。
例如，免疫脂质体可以将活性剂特异性地递送到具有由免疫脂质体的抗体部分识别的独特抗原标志物的细胞。由于制造简单和细胞特异性，在理想情况下，免疫脂质体用于将活性剂体内递送到靶组织。
肌肉细胞特异性抗体、脂肪细胞特异性抗体、肝细胞特异性抗体和其它体细胞特异性类型的抗体可以与抑制剂或含有抑制剂的脂质体结合使用，以帮助将抑制剂和脂质体靶向具体细胞类型。此类脂质体中也可以包含其它活性剂。
在一些情况下，活性剂可以结合惰性稀释剂或可同化的可食用载体等药学上可接受的媒剂口服施用。所述活性剂可以包封在硬壳或软壳明胶胶囊中、压成片剂或者直接与患者饮食中的食物一起掺入。对于口服治疗施用，所述活性剂可以与一种或多种赋形剂组合，并以可摄入的片剂、口含片剂、锭剂、胶囊、酏剂、悬浮液、糖浆、薄片等形式使用。此类组合物和制剂可以含有至少0.1％的活性化合物。当然，组合物和制剂的百分比可以变化。对于这类治疗，有用组合物中的化合物用量需达到有效剂量水平。
还可以将活性剂掺入片剂、锭剂、丸剂和胶囊剂等剂型中。这些剂型还可以含有以下任何一种：黄蓍胶、阿拉伯胶、玉米淀粉或明胶等粘合剂；磷酸二钙等赋形剂；玉米淀粉、马铃薯淀粉、海藻酸等崩解剂；硬脂酸镁等润滑剂；含有纤维素的聚合物(例如，羟丙基甲基纤维素、甲基纤维素、乙基纤维素)、聚乙二醇、聚谷氨酸、聚天门冬氨酸或聚赖氨酸等聚合物；并且可以添加乳糖或阿斯巴甜等甜味剂或薄荷、冬青油或樱桃香料等调味剂。
片剂调配物可以包含以下中的一种或多种：乳糖、蔗糖、甘露醇、山梨糖醇、磷酸钙、玉米淀粉、马铃薯淀粉、微晶纤维素、明胶、胶体二氧化硅、滑石、硬脂酸镁、硬脂酸和其它赋形剂、着色剂、填料、粘合剂、稀释剂、缓冲剂、润湿剂、防腐剂、调味剂、染料、崩解剂和药学上相容的载体。锭剂形式可以包括调味剂或甜味剂中的活性剂，例如以及包括惰性基质中的活性剂的糖锭，如含有本领域可获得载体的明胶和甘油或蔗糖和金合欢乳液、凝胶等。
当单位剂型是胶囊时，除了上述类型的材料外，锭剂形式还可以含有如植物油或聚乙二醇等液体载体。各种其它材料可以以包衣或以其它方式改变固体单位剂型的物理存在形式。例如，片剂、丸剂或胶囊可以用明胶、蜡、虫胶或糖等包衣。糖浆或酏剂可含有活性化合物、作为甜味剂的蔗糖或果糖、作为防腐剂的甲基和对羟基苯甲酸丙酯、染料和樱桃或橙子香精等调味剂。用于制备任何单位剂型的任何材料在所采用的量方面应当是药学上可接受的，并且基本上无毒。另外，活性化合物和药剂可以掺入到缓释制剂和装置中。
有用的固体载体包含细碎的固体，如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。有用的液体载体包含水、醇或二醇或水-醇/二醇共混物，其中，任选地，本发明的化合物可以在有效水平上借助无毒表面活性剂进行溶解或分散。通过添加如芳香剂和额外抗微生物剂等佐剂，可以优化给定用途的性质。
合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、经改性纤维素或经改性矿物材料等增稠剂也可与液体载体一起使用，形成可涂抹的糊剂、凝胶、油膏、肥皂等，直接涂抹在使用者的皮肤上。
在一些实施例中，活性剂中的一种或多种活性剂与聚乙二醇(PEG)连接。例如，本领域的技术人员可以选择将活性剂与PEG连接，形成以下聚乙二醇化药物。
通过例如本文所述的比较其体外活性和动物模型中的体内活性，可以确定活性剂(例如，PIP4K降解剂)的有用剂量。本领域中可以采用的方法是，将小鼠和其它动物的有效剂量外推到人；例如参见第4938949号美国专利。药剂易于以单位剂型施用。
所需剂量易于以单个剂量或以适当间隔施用的分次剂量形式呈现，例如以每天两个、三个、四个或更多个亚剂量呈现。例如，亚剂量本身可以进一步分成许多离散的松散间隔进行施用；如多次口服、腹膜内或静脉内给药。例如，可以期望的是，本发明的组合物可通过连续输注或以单独剂量，在延长的时间段内进行静脉内注射。
治疗有效量的活性剂(例如，PIP4K降解剂)必然会随着待治疗受试者和疾病、疾病严重程度或生理问题而变化。本领域技术人员将会认识到，所述用量可以根据施用方法而变化。活性剂(例如，抑制剂)治疗用量不仅会随着施用途径而变化，还会随着被治疗病状的性质以及患者的年龄和病状而变化，最由主治医师或临床医生决定。
本发明的药物组合物可以包含有效量的本发明活性剂中的至少一种活性剂(例如，PIP4K降解剂)，或本发明的两种或更多种不同药剂(例如，两种或更多种PIP4K抑制剂或降解剂)。这些组合物还可以包含药学上有效的载体。
本发明的药物组合物还可以包含其它活性成分和治疗剂，例如抗糖尿病剂、抗炎剂、镇痛剂、维生素等。将本文公开方法中的任何方法和组合物中的任何组合物与常规糖尿病疗法和各种药物进行组合，以增强此类方法和/或组合物的功效，也属于本发明的范围内。例如，含有活性剂的组合的方法和组合物可以通过不同的机制起作用，从而提高治疗的功效或速度。含有活性剂的组合的方法和组合物还可以降低常规疗法的剂量/毒性，和/或增加常规疗法的敏感性。
例如，胰岛素或糖尿病药物的各种药物制剂可以与本文所述的方法和组合物组合使用。例如，以下任何一种药物均可与本文所述的方法和组合物一起用于治疗糖尿病：如常规胰岛素(如
)、异烷胰岛素(表示为NPH)、胰岛素锌悬浮液(如
和
)，以及双相低精蛋白锌胰岛素(如
)。同时还开发了针对特定的作用模式，即采用快速作用或延长作用设计的人胰岛素类似物和衍生物。可以使用长效胰岛素类似物，德谷胰岛素(degludec)(BeginTM)以及德谷胰岛素和速效门冬胰岛素的双相制剂，DegludecPlus(BOOSTTM)。包括速效胰岛素类似物的可商购获得的胰岛素制剂中的一些胰岛素制剂包含
(B28Asp人胰岛素的制剂)、
(B28LysB29Pro人胰岛素的制剂)和
(B3LysB29Glu人胰岛素的制剂)。包括长效胰岛素类似物的可商购获得的胰岛素制剂中的一些胰岛素制剂包含
(甘精胰岛素的制剂)和
(地特胰岛素的制剂)。
单克隆抗体、核酸抑制剂和基因疗法均为靶向型疗法，所述靶向型疗法还可以组合到PIP4K抑制剂组合物中，并用于本文所述的方法。
在制造和储存条件下，最终剂型应具有无菌性、呈流体状和具有稳定性。
试剂盒
本发明的另一方面是用于抑制PIP4K或治疗胰岛素抵抗和糖尿病的一种或多种试剂盒。
本发明的试剂盒可以包含PIP4K抑制剂、用于修饰基因组PIP4K位点的试剂或其它治疗剂或其组合。试剂盒还可以包含用于施用PIP4K抑制剂、用于修饰基因组PIP4K位点的试剂或其它治疗剂的说明书。
在一些情况下，试剂盒可以包含用于从受试者中分离细胞(例如肌肉、肝、脂肪、神经和/或其它类型的细胞)并修饰基因组PIP4K位点的试剂。此类试剂盒可以包含用于从受试者中分离细胞的无菌器具、用于培养细胞的试剂、用于靶向基因组PIP4K位点的一个或多个向导RNA、用于将经修饰的细胞施用回给受试者的器具及其任何组合。
以下非限制性实例展示了用于开发本发明的材料和方法。附录A可以提供额外信息。
实例1：材料和方法
此实例展示了本发明开发中使用的材料和方法中的一些材料和方法。
细胞系，认证：
细胞系购自ATCC和/或用亚利桑那大学(University of Arizona)遗传学核心进行指纹采样。使用龙沙公司(Lonza)生产的Mycoalert，测试细胞是否不含支原体。
细胞培养条件：
使用补充有10％FBS、谷氨酰胺和丙酮酸盐的DMEM培养基，培养293T、HeLa、PaTu8988t和BJ细胞。在RPMI培养基中培养H1299和H1975细胞。
细胞裂解和免疫印迹：
在补充有1片蛋白酶和磷酸酶抑制剂的RIPA缓冲液中裂解细胞。在冰上培养20分钟后，通过以14,000x g离心清除裂解物，并且使用BCA测定，对上清液进行量化。使用NovexNuPAGE系统，进行裂解物SDS-PAGE。在4-12％Bis Tris预制凝胶和10％Bis Tris凝胶上，使用MOPS缓冲液，分离蛋白质。在350mA下，将蛋白质转移到0.45μm硝酸纤维素膜上，并持续1小时。膜在含5％脱脂牛奶的TBST中封闭，并与第一抗体培养过夜：为了化学发光检测抗体结合，用HRP缀合的第二抗体对膜进行印迹。使用ECL溶液使膜显影，并将膜暴露于胶片。对于胰岛素信号传导蛋白，修改方案，使细胞在triton缓冲液中裂解，使用二级IRDye进行LiCor Odyssey检测，并用Image Studio Lite软件进行量化。
产生慢病毒，病毒转导：
293T细胞用于产生慢病毒。一旦细胞在10cm培养皿中90-95％汇聚，就用Opti-mem、Lipofectamine 2000、慢病毒载体和辅助质粒VSVG以及Δ8.2进行转染。转染后2天和3天，收获病毒上清液，然后过滤，并在4℃下在超速离心机中以25,000rpm浓缩120分钟。
产生具有CRISPR敲除PIP4K的细胞系：
将pX458中的CRISPR导向转染到293T细胞中。在转染后48-96小时，使用WCMC流式细胞术核心的Influx分选器在96孔板中对GFP阳性细胞进行单细胞分选。两周后，对孔进行评分，以含有单细胞集落，扩大，以筛选出成功的PIP4K2A/PIP4K2B/PIP4K2C敲除。通过蛋白质印迹，PCR在每个切割位点周围进行验证。
产生具有miRE敲减PIP4K的细胞系
将含有所需miR-E shRNA的LT3GEPIR载体在现有shRNA下游用EcoRI-HF/MluI-HF进行双重消化，并进行PCR纯化。将待添加的miR-E序列用Multi-sh-F和Multi-sh-R进行PCR扩增。对PCR产物进行纯化，用BbsI/MluI进行双重消化，并再次进行PCR纯化。使用T4连接酶用PCR产物和开放的LT3GEPIR载体进行连接。使用miRE-F筛选集落。表1中列出了所采用的引物。
表1：核酸、引物等。
产生哺乳动物和细菌表达载体：
为了产生用于表达PIP4K异构体的抗发夹编码序列载体，将野生型PIP4K2A和PIP4K2C克隆到具有PGK启动子的慢病毒骨架中。然后，在摆动位置使用QuikChange为抗发夹cDNA制作激酶死亡的变体和沉默突变，在PIP4K cDNA中产生突变。表1中列出了所采用的引物。由于所有发夹都针靶向3'UTR，所以PIP4K2C cDNA无需摆动突变，。为了产生PIP4K2CN端突变体，使用安捷伦公司(Agilent)生产的Quikchange试剂盒(220521)，见表1。
高效液相色谱法测定磷酸肌醇：
细胞磷酸肌醇在补充有谷氨酰胺、10％透析的FBS和10μCi/mL 3H肌醇(myo-inositol)的不含肌醇(inositol)的DMEM中代谢标记48小时。用PBS洗涤细胞，然后将细胞转移到冰上。杀伤细胞，然后用1.5mL冰冷水溶液(1M HCl、5mM四丁基硫酸氢铵、25mM EDTA)刮擦，从而收获细胞。每个样本中加入冰冷的2mL MeOH和4mL CHCl3。确保每个小瓶盖紧后，对样本进行涡旋处理，然后以1000rpm离心5分钟。如果可见明显的中间层，则轻轻搅拌样本并再次旋转，直到产生两个透明层。使用理论上部清洗有机层(下部)，同时使用理论下部清洗水性层(理论上部和下部与CHCl3:MeOH:水溶液按8:4:3的体积比组合制成)。收集有机相并在氮气下干燥。使用一甲胺溶液(47％甲醇、40％甲胺中的36％甲胺、9％丁醇和8％H2O，按体积计)对脂质进行脱酰化处理。样本在55°下培养1小时，随后在氮气下干燥。向干燥的小瓶中添加1mL理论上部和1.5mL理论下部(理论上部和下部与CHCl3:MeOH:H2O按8:4:3体积比组合制作)。对样本进行涡旋处理，并以1000rpm旋转。收集水相(上部)，并在氮气下干燥。将样本重新悬浮在150μL缓冲液A(1mM EDTA)中，然后过滤并转移到安捷伦聚丙烯管。使用Partisphere SAX柱，通过阴离子交换HPLC分析样本。用以100％缓冲液A(1mM EDTA)开始并且随时间增加缓冲液B(1mM EDTA、1M NaH2PO4)的梯度洗脱化合物：0-1分钟100％缓冲液A、1-30分钟98％缓冲液A/2％缓冲液B、30-31分钟86％缓冲液A/14％缓冲液B、31-60分钟70％缓冲液A/30％缓冲液B、60-80分钟34％缓冲液A/66％缓冲液B、80-85分钟100％缓冲液B、85-120分钟100％缓冲液A。缓冲液通过柱以1毫升/分钟的速度泵送。HPLC柱的洗脱液流入在线连续流动闪烁检测器进行同位素检测。设置检测器，观察10分钟到85分钟之间的事件，闪烁液以4毫升/分钟流动。
使用LCMS测量磷脂酸：
使用与所述磷酸肌醇分析方法相同的方法提取细胞脂质。在耦接到配有Phenomenex Luna二氧化硅
柱的安捷伦1260HPLC的安捷伦6230电喷射离子化-飞行时间(ESI-TOF)MS上进行分析之前，将脂质干燥，并用113μL氯仿:甲醇:水(73:23:3)的混合物进行稀释过滤(0.45μm)。使用具有二元梯度洗脱系统的正相HPLC执行LCMS分析，其中溶剂A为氯仿:甲醇:氢氧化铵(85:15:0.5)，溶剂B为氯仿:甲醇:水:氢氧化铵(60:34:5:0.5)。9分钟内，利用从100％A到100％B的线性梯度实现分离。利用在阳性模式下运行的双ESI源，检测磷脂物种，在m/z 100-1700的扩展动态范围内，以每秒一个光谱的速度进行采集；气体温度：325℃；干燥气体10升/分钟；雾化器：20psig；碎裂电压300V。
免疫沉淀：
将表达3xHA空载体或3xHA-PIP5K1A的293T细胞系在4％PFA中固定10分钟，用PBS洗涤3x，并且在裂解缓冲液(10mM Tris 7.4、150mM NaCl、0.5mM EDTA、0.5％NP40)中使用探针超声仪裂解2分钟。使用对照磁珠，在4°下对裂解物进行1小时预清除处理，并添加皮尔斯磁性抗HA磁珠，在4°下培养过夜。磁珠用裂解缓冲液洗涤3遍，并且将等分试样添加到含有β巯基乙醇的样本缓冲液上样染料中，煮沸并在SDS-聚丙烯酰胺凝胶电泳上运行，进行免疫印迹。
蛋白质纯化：
使用具有PIP4K异构体编码序列变体的pGEX载体，对BL21细菌细胞进行转染。细胞在37°下以200rpm在1L TB中生长至外径0.8，此时添加500uL 1M IPTG。将培养物在室温下振荡过夜进行蛋白质诱导，并以5000g丸粒化处理15分钟。对细胞进行裂解(50mM Tris pH7.5、500mM NaCl、10mM MgCl2、10％甘油、DTT、溶菌酶、蛋白质/磷酸酶抑制剂)，超声处理1分钟(输出4，连续工作循环)，并以10,000g旋转沉降1小时。根据制造商的方案，使用谷胱甘肽琼脂糖珠，保留上清液进行进一步纯化和切割。
体外激酶测定：
对细胞进行胰蛋白酶消化，并进行细胞数正常化。在HNE缓冲液(20mM HEPESpH7.4、100mM NaCl、0.5mM EGTA)中重新悬浮细胞团块或大肠杆菌(E.coli)纯化蛋白质，在32P-γ-ATP和脂质体(10ug PS、含1ug PI(4)P的30mM HEPES pH 7.4、1mM EGTA)存在的情况下进行超声处理。脂质体脂质购自Avanti公司。通过添加50uL4N HCL终止反应。为了提取脂质，添加100μL MeOH:CHCl3(1:1)，对样本进行涡旋处理2次，并持续30秒。以最高速度旋转沉降样本2分钟，并且使用1-丙醇:2N乙酸(65:35v/v)的薄层色谱法(TLC)分离含有磷脂酰肌醇脂质的有机相(底层)。使用1％草酸钾包衣，提前制备TLC板。通过放射自显影，在GETyphoon FLA 7000上进行磷酸化脂质的可视化，并使用ImageQuant TL软件进行量化。
GST拉下测定
如上文所述，分离GST标记蛋白质，但是洗涤后须将具有结合蛋白的磁珠的等分试样添加到293T细胞裂解物中，该293T细胞裂解物通过在IP缓冲液(50mM Tris-Cl pH 8.0、150mM NaCl、1％NP-40、用EDTA完成PI/Pis)中裂解并以22,000xg×10分钟旋转出DNA产生。这些裂解物和纯化蛋白质在4度温度下共同培养1小时，之后再次进行珠沉淀，用IP缓冲液洗涤三次，用2M NaCl洗脱，并且利用SDS PAGE和蛋白质印迹进行分析。
荧光显微法
293T细胞在用聚-d-赖氨酸预处理的玻璃盖玻片上生长。用pH 7.4的磷酸盐缓冲盐水(PBS)冲洗粘附细胞系，随后在-20MeOH中固定/渗透20分钟。固定后，将细胞在封闭缓冲液(含3％BSA的PBS)中封闭30分钟，并用第一抗体在室温下于封闭缓冲液中标记1小时。盖玻片用封闭缓冲液洗涤三次，并在室温下于封闭缓冲液中与Alexa荧光缀合的山羊第二抗体共同培养1小时。在与第二抗体共同培养后，用PBS洗涤盖玻片三次，用水洗涤一次，然后将盖玻片装在具有带DAPI的Prolong Gold的玻璃显微镜载玻片上。使用以下第一抗体：LAMP1。以1:1000使用Alexa荧光缀合第二抗体(赛默飞世尔科技公司(ThermoScientific)。在配备有Andor Zyla sCMOS相机的尼康(Nikon)Eclipse Ti显微镜上获取荧光和相衬图像。在每次实验中，曝光时间全程保持恒定并且在线性范围内。使用60×油浸物镜时，利用AutoQuant进行图像堆叠和去卷积。
qRT-PCR
使用RNeasy制备总RNA。使用Superscript Vilo合成cDNA，并且利用固绿SYBR和Realplex Mastercycler执行qRT-PCR。所使用的引物列表参见表1中的寡核苷酸。对mRNA和qPCR进行的分离如下。将200,000个细胞铺板于6孔塑料培养皿中。24小时后，使用RNeasy方案提取裂解物中的RNA。在50μl H2O中以1μg/μL的浓度重悬RNA。使用SuperScript Vilo转录cDNA。表1中给出了PCR反应中用作引物的寡核苷酸的序列。前文表明，此处量化的基因由TFEB调节。
定量和统计分析
用至少三个生物复制品重复实验，但以下情况例外：图3N-3Q中的实验执行一次，具有误差条的组进行三次技术重复；2)图4G-4K中的实验执行一次。分析中未排除任何样本。在对两组进行比较时，使用双尾t检验。P值如附图说明所示。在对两个以上的组进行比较时，使用ANOVA和Holm-Sidack事后检验计算显著性。附图说明指出了哪些比较是显著的以及相应的p值。
表2：资源
实例2：PIP4K家族成员的丢失不影响细胞活力
本实例展示了使用短发夹RNA(shRNA)抑制剂减少不同PIP4K家族成员不会影响细胞活力。
为了研究PIP4K酶在细胞信号传导中的作用，生成了几种工具，以系统地耗尽PIP4K家族的单独成员。首先，克隆了一系列基于慢病毒的串联的基于miRE的短发夹RNA(shRNA)(表1-3)，并且在HeLa细胞以及其它人永生化或转化细胞中诱导PIP4K家族异构体的稳定敲减(图1A、图1L-1M；图2K-2N)(Fellmann等人，2013；Fellmann等人，2011；Pelossof等人，2017)。
表3：靶向shRNA发夹/CRISPR向导序列的PIP4K异构体
表4：细胞系注释
| 细胞系 | 发夹/向导ID | 耗尽的/缺失的蛋白质 |
| Ren | Ren | 无 |
| Ren2 | Ren；Ren | 无 |
| Ren3(对照) | Ren；Ren；Ren | 无 |
| A1 | A650 | PIP4K2A |
| A2 | A665 | PIP4K2A |
| B1 | B130 | PIP4K2B |
| B2 | B868 | PIP4K2B |
| C1 | C1406 | PIP4K2C |
| C2 | C3036 | PIP4K2C |
| AB1 | A650；B868 | PIP4K2A/2B |
| AB2 | A665；B130 | PIP4K2A/2B |
| BC1 | B130；C3165 | PIP4K2B/2C |
| BC2 | B868；C1406 | PIP4K2B/2C |
| AC1 | A650；B868 | PIP4K2A/2C |
| AC2 | A665；B130 | PIP4K2A/2C |
| ABC1(TKD1) | A650；B130；C1406 | PIP4K2A/2B/2C |
| ABC2(TKD2) | A665；B868；C3036 | PIP4K2A/2B/2C |
| ABC3 | A948；C3165 | PIP4K2A/2B/2C |
| WT | g_PIP4K2A-1/2B-1/2C-1 | 无 |
| TKO1 | g_PIP4K2A-2/2B-2/2C-1 | PIP4K2A/2B/2C |
| TKO2 | g_PIP4K2A-1/2B-1/2C-1 | PIP4K2A/2B/2C |
| TKO3 | g_PIP4K2A-1/2B-2/2C-1 | PIP4K2A/2B/2C |
shRNA介导的PIP4K中的一种或所有的沉默并未导致形态的总变化，或使所检查细胞的生长速率发生重大变化(图1O)。作为正交方法，CRISPR/Cas9用于使HEK293T细胞中的PIP4K2A、PIP4K2B和PIP4K2C缺失(图1B，表3-4)，并得出类似的结果。
实例3：PIP4K的丢失导致PI(5)P水平增加、PI3K活化增加以及自噬缺陷
PIP4K2A/B/C三重敲除293T细胞(下文为TKO)和三重敲减HeLa细胞(下文为TKD)重现了先前报告的PIP4K酶耗尽情况下的表型。根据报告(Gupta等人，2013)，三种酶的丢失均使其底物PI(5)P增加了两倍(图1C-1D)。另外，在胰岛素刺激后，TKD细胞出现PI3K信号传导增加(图1E)，这与在Pip4k2b-/-小鼠中胰岛素敏感性增加的观察结果一致(Carricaburu等人，2003；Lamia等人，2004)。此外，由于自噬体-溶酶体融合存在缺陷，293T TKO细胞积聚了LAMP1溶酶体，如Pip4k2a-/-、Pip4k2b-/-小鼠胚胎成纤维细胞(MEF)所述(图1F)(Lundquist等人，2018)。
实例4：细胞PI(4,5)P2在PIP4K耗尽后增加
有趣的是，细胞中三种PIP4K的耗尽改变了磷酸肌醇的水平，超过了PI(5)P。在TKD细胞和TKO细胞中，均观察到PI(4,5)P2的惊人增加，同时伴随PI(4)P的减少(图1G-1J、2P-2Z)。在培养物中，PI(3,4,5)P3生长期间的基础水平通常低于基于HPLC的测定的检测限。然而，本发明人能够检测到TKO细胞中PI(3,4,5)P3的基础升高，这表明PI3K可以利用增加的PI(4,5)P2(图1K)。
PI(4,5)P2约占所有磷酸肌醇的50％，但是大多数磷酸肌醇与细胞结构、迁移和粘附所需的细胞骨架和支架蛋白结合(Brown，2015；Choi等人，2015)。虽然PI(4,5)P2高度丰富，但是通过PIP5K局部产生PI(4,5)P2，即可对通过PI3K和PLC路径的信号传导进行时空控制(Choi等人，2015；Saito等人，2003；Xie等人，2009)。
实例5：PIP4K在PI(4)P和PI(4,5)P2内稳态中的非催化依赖性作用
PIP4K家族的成员具有显著不同的催化速率。例如，PIP4Kα(PIP4K2A)的活性比PIP4Kγ(PIP4K2C)的活性高1000倍，即近酶促死亡(Clarke和Irvine，2013)。在对具有单敲减或双敲减PIP4K异构体的细胞中进行的PI(4,5)P2水平的分析表明，在所有三种异构体中，累加效果与相对催化活性无关(图2A-2B)。最活跃的异构体PIP4Kα/β的双敲减没有表型复制三重敲减，这表明催化活性不是调节PI(4,5)P2水平的最重要因素。为了评估PIP4K酶的催化活性对PI(4,5)P2调节是否重要，产生了shRNA抵抗HA标记的激酶活性或激酶死亡的PIP4K异构体(图2C-2D)。
令人惊讶的是，激酶活性或激酶死亡(PIP4K2AKD)的PIP4K表达挽救了PI(4,5)P2水平(图2E-2F)。此外，PI(4)P水平还回到基线，其中活性或激酶死亡PIP4K2A在TKD细胞系和TKO细胞系两者中均进行表达(图2G-2H)。相比之下，只有活性PIP4K2A恢复了正常PI(5)P水平，这表明与PI(4,5)P2相比，由于PIP4K酶活性的丢失，导致敲减这种脂质物种在细胞中的含量升高(图2I-2J)。
利用3'IRES-GFP标签，对具有低表达和高表达的PIP4K2AKD群体的细胞群进行分选：分别为PIP4K2AKD_低和PIP4K2AKD_高(图3N)。这些细胞系的HPLC分析表明，PI(4,5)P2的剂量依赖性降低和PI(4)P增加与PIP4K2AKD表达水平相关(图3O-3P)。
这些数据表明，在维持细胞PI(4)P和PI(4,5)P2水平的内稳态方面，PIP4K具有非催化依赖性作用，这与其将PI(5)P转化为PI(4,5)P2的酶功能不同。
实例6：PIP5K活性在耗尽PIP4K的细胞中升高
根据观察，PI(4,5)P2相对于PI(4)P的增加与通过PIP5K稳健产生PI(4,5)P2相一致。在机械破碎的细胞中，测量PIP5K的活性。本发明人观察到，TKO细胞表现出PIP5K活性升高，这与在PIP4K不存在的情况下更活跃的PIP5K模型相一致。在表达活性或激酶死亡的PIP4K异构体的细胞中，增加的PIP5K活性发生反转，这表明PIP5K活性不依赖于这些蛋白质的酶活性(图3A)。
PIP5K的所有三种异构体都受到磷脂酸(PA)和与如Rac等G蛋白缔合的刺激(Jenkins等人，1994；Weernink等人，2004)。然而，PIP5K在PIP4K耗尽细胞中的活化并非由这些上游效应子引起，因为具有PIP4K敲减的细胞没有表现出PA水平增加(图3D)，并且Rac1的敲除不具备消除PIP4K调节PI(4)P和PI(4,5)P2水平的能力。此外，PIP5K1A和PIP5K1C的蛋白质水平不会为了响应PIP4K家族的敲减或敲除而发生一致性改变。
在掩盖PI(5)P并由此降低可以抑制PIP5K活性的衔接子蛋白的可用性方面，本发明人还考虑到PIP4K具有非催化依赖性作用的可能性。为了检验增加的PI(5)P可用性是否可以增强PIP5K活性从而降低PI(4)P与PI(4,5)P2的比率，用编码肌醇磷酸磷酸酶(Ipgd)(识别PI(4,5)P2的细菌4-磷酸酶)的转基因转染细胞。虽然将Ipgd转染到293T细胞中会使细胞PI(5)P急剧增加，但是细胞磷酸肌醇的HPLC分析并未表明PIP5K活性随之增加。PI(5)P在具有完整PIP4K(WT)的细胞中的可用性增加不会导致PI(4)P与PI(4,5)P2的比率降低。另外，将Ipgd引入TKO细胞会使PI(5)P大幅增加，但并未改变所测量的PI(4)P或PI(4,5)P2水平。
这些结果表明，PI(5)P的可用性不会介导观察到的PIP5K活性变化。
实例7：通过在带负电的膜的表面上的直接相互作用，PIP4K可以抑制PIP5K
据报告，PIP4K和PIP5K家族成员之间存在物理相互作用(Hinchliffe等人，2002；Huttlin等人，2017)。此类相互作用将为PIP4K直接抑制PIP5K提供时机。值得注意的是，PIP4K家族成员比PIP5K家族成员丰富得多，有利于PIP4K通过化学计量比抑制PIP5K(Itzhak等人，2016；Wisniewski等人，2014)。
为了检验在PIP4K耗尽细胞中的PIP5K活性改变是否由这两个激酶家族之间物理相互作用中断导致，用经纯化的蛋白质测量了体外激酶活性。如图3B所示，所有三种PIP4K异构体都可以直接抑制PIP5K2A催化的PI(4)P到PI(4,5)P2的磷酸化作用。为了消除来自PIP4K纯化的小分子污染物可能抑制PIP5K1A的可能性，将PIP4K2C煮沸。如图3C所示，煮沸的变性PIP4K2C无法再抑制PIP5K1A。为了研究膜双层部位是否发生PIP4K与PIP5K之间的相互作用，用洗涤剂重复实验，消除PI(4)P-脂质体的形成。Triton-X100胶束中呈现的磷酸肌醇增强了PI4K等一些PI激酶的活性(Guo等人，2003)，但在此情况下，PIP5K1A活性总体上有所降低。重要的是，添加洗涤剂消除了PIP4K2A抑制PIP5K1A的能力(图3D)。这些数据表明，需要将两种蛋白质募集到膜表面，以介导抑制性相互作用。使用相对于两种酶的水平大量摩尔过量的底物PI(4)P执行此测定，因此本发明人假定通过PIP4K隔离PI(4)P不太可能解释此类抑制。鉴于PIP4K和PIP5K缔合的膜依赖性，在洗涤剂存在的情况下，用PIP4K与PIP5K进行共免疫沉淀的尝试失败。然而，图3F-3G示出了在完整细胞中使用化学交联的实验中，以近内源性水平表达的3xHA标记的PIP5K1A与内源性PIP4K2A的相互作用。此外，GST-PIP4K2C缀合的谷胱甘肽珠拉下了293T裂解物中的大多数PIP5K1A，但仅拉下了一小部分PIP5K1C(图3G-3H)，这个结果支持了PIP4K与PIP5K1A在细胞中相互作用以调节PI(4,5)P2水平的假设。
为了进一步限定此相互作用的性质，产生PIP4K2C变体，并评估其在体外抑制PIP5K1A活性的能力。人PIP4K2A(PDB 2YBX)和PIP4K2C(PDB 2GK9)已经结晶，而唯一结晶的PIP5K家族成员来自斑马鱼(Danio rerio)，并且所述家族成员形成的晶体结构类似于PIP4K蛋白(PDB 5E3S)的晶体结构(Muftuoglu等人，2016)。有趣的是，PIP4K2C通过两个二聚体的并排相互作用结晶为四聚体，其中所有四个催化袋都出现在带正电的四聚体的同一侧。
诱变工作主要集中在PIP4K2C，在COSMIC数据库中，在PIP4K2C的aa132之后，从携带移码突变的截断突变体开始诱变(参见网站cancer.sanger.ac.uk/cosmic)。在体外抑制PIP5K1A活性的能力方面，这种保持参与二聚体相互作用以及四聚体相互作用两者的残基截短突变体与全长PIP4K2C一样强效(图4G)。
本发明人探索了PIP4K2C的前132个残基，并鉴定了面向四聚体结构中相反二聚体的两个区：氨基酸69-75(VMLLPDD，SEQ ID NO:93)和氨基酸89-95(FHRENLP，SEQ ID NO:94)(图3I)。在GST-PIP4K2C内，将74DD突变为74NN或将91REN突变为91EED并不能阻止此蛋白质抑制PIP5K1A(图4H)。然而，在此区中引入可能损害整个二聚体/二聚体相互作用(VMLLPDD(SEQ ID NO:93)到EIFLPNN(SEQ ID NO:95)的疏水性相互作用和电荷相互作用两者的突变，以下称为PIP4K2CVD，导致丢失与PIP5K1A的相互作用(图3J)。此外，PIP4K2CVD未能在保持PIP4K活性的同时抑制PIP5K1A活性(图3M)(图4I-4J)，证实了所述蛋白质为折叠蛋白质并具有功能性。为了证实PIP4K与PIP5K1A之间这种相互作用是在CRISPR敲除细胞中观察到的PI(4,5)P2增加的生理机制，如前所述，用PIP4K2CVD或野生型PIP4K2C重建TKO细胞(图4K)。值得注意的是，PIP4K2CVD突变体未能使三敲除细胞中观察到的PI(4)P减少和PI(4,5)P2增加反转(图3L-3M)，这一结果与本发明人已经在体外观察到的未能与PIP5K1A相互作用或对其进行抑制相一致。
这些结果揭示了PI(4,5)P2产生的调节机制，由此PIP5K1A通过与PIP4K N端基序VMLXPDD(SEQ ID NO:96，其中X为任何氨基酸)的直接相互作用而受到负调控。一部分细胞PIP4K直接与PIP5K酶在富含PI(4)P的膜处相互作用，并且用于减弱PIP5K介导的PI(4)P到PI(4,5)P2的转化。
实例8：PIP4K在调节PIP5K中的结构作用，并且PI3K路径不同于其在自噬中的催化作用
PI(4,5)P2的水平在其前体PI(4)P的扰动下非常稳定(Nakatsu等人，2012)，但如图1G-1J所示，PIP4K家族成员的耗尽导致PI(4)P和PI(4,5)P2发生近两倍的变化。PI3K路径的胰岛素活化始于质膜，其中PI(4,5)P2转化为PI(3,4,5)P3募集效应蛋白Akt和Pdk1，以传播信号传导级联。
本发明人假设，在PIP4K耗尽的细胞中，增加的PI(3,4,5)P3可能归因于由于其底物PI(4,5)P2的产生增加引起的PI3K路径活化。事实上，在急性刺激期间，通过PIP5K1A局部产生PI(4,5)P2维持了B细胞、角质细胞和乳腺癌中PI3K路径的活化(Choi等人，2016；Saito等人，2003；Xie等人，2009)。
脂质HPLC分析表明，在急性胰岛素刺激时，PIP4K敲除细胞的PI(3,4,5)P3增加了四倍(图4A)。与PIP4K利用PIP5K对PI(4,5)P2合成的非催化依赖性抑制来抑制胰岛素信号传导的模型一致，TKO细胞中激酶死亡的PIP4K2A或近激酶死亡PIP4K2C的表达能够使PI(3,4,5)P3积聚的胰岛素依赖性增加反转。重要的是，PIP4K2CVD突变体的表达未能挽救PI(3,4,5)P3水平(图4A)，这与介导PI3K路径的负调节VMLXPDD(SEQ ID NO:96)基序一致。
进一步地，根据通过AKT的S473磷酸化以及AKT介导的PRAS40磷酸化进行的判断，HeLa TKD细胞展现出增强的PI3K路径活化(Manning和Toker，2017)(图4B-4C)。无论通过PI(3,4,5)P3水平测量还是通过AKT活化测量，PIP4K2AKD或PIP4K2C的表达都能使增强的胰岛素敏感性反转。本文提供的结果表明，通过消除PIP4K异构体增加PIP5K活性会驱动质膜池中PI(4,5)P2的过度产生，在胰岛素信号传导期间，PI3K可以使用所述PI(4,5)P2。
之后，本发明人询问先前报告的PIP4K2A在介导自噬中的作用是否需要PIP4K的非催化功能(Lundquist等人，2018)。PIP4K的丢失导致LAMP1阳性溶酶体积聚和TFEB靶向基因的转录增加(图4D-4F)。然而，与磷酸肌醇中观察到的变化不同，只有用活性PIP4K2A而非激酶死亡PIP4K2A进行的重建才能显示出自噬调节已经恢复(图4D-4F)。总之，这项工作突出强调了PIP4K酶的复杂性和多功能性。
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本文参考或提及的所有专利和出版物表示本发明所属领域技术人员的技术水平，并且每个此类参考专利或出版物据此具体通过本发明的整体引用，成为本发明的一部分，其程度如同其已经单独通过整体引用，成为本发明的一部分，或整体在本文中阐述。申请人保留使来自任何此类引用专利或出版物的任何和所有材料以及信息实际成为本说明书一部分的权利。
以下声明旨在根据说明书中的前述说明来描述和总结本发明的各个实施例。
声明：
1.一种方法，包括在受试者中耗尽、降解或抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体。
2.根据声明1所述的一种方法，其能够减少糖尿病、代谢综合征、胰岛素抵抗、肥胖症、癌症、免疫缺陷、自身免疫性疾病、感染或其组合的发作或严重程度。
3.根据声明1或2所述的一种方法，其能够增强受试者中的胰岛素信号传导。
4.根据声明1、2或3所述的一种方法，其中，耗尽、降解或抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体减少了一种或多种异构体与至少一种其它PIP4K或PIP5K发生支架作用或相互作用。
5.根据声明1到3或4所述的一种方法，其中，所述一种或多种磷脂酰肌醇-5-磷酸4-激酶异构体是PIP4K2A、PIP4K2B或PIP4K2C。
6.根据声明1到4或5所述的一种方法，其中，降解一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括删除一个在一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体内包含SEQ ID NO:5或96的序列。
7.根据声明1到4或5所述的一种方法，其中，降解一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括使结合部分接触所述一种或多种异构体，其中，所述结合部分与药剂直接或间接连接，药剂向细胞发出信号降解与药剂结合的磷脂酰肌醇-5-磷酸4-激酶。
8.根据声明7所述的一种方法，其中，向细胞发出信号降解与药剂结合的磷脂酰肌醇-5-磷酸4-激酶的所述药剂是一种E3泛素连接酶。
9.根据声明7或8所述的一种方法，其中，所述结合部分是一种与所述磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体之一特异性结合的小分子、抗体、肽、多糖或脂质。
10.根据声明7、8或9所述的一种方法，其中，所述结合部分通过氢键合、疏水相互作用、空间相互作用、亲水相互作用或其组合与药剂间接连接。
11.根据声明7到9或10所述的一种方法，其中，间接连接指所述结合部分与药剂之间的相互作用发生在所述结合部分接触磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体之一之前。
12.根据声明7到10或11所述的一种方法，其中，间接连接指所述结合部分与药剂之间的相互作用发生在所述结合部分与磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体之一接触之后。
13.根据声明1到11或12所述的一种方法，其中，降解一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括使一种或多种异构体接触对磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体之一具有特异性的抗体，其中，所述抗体具有一种可结合E3泛素连接酶的Fc结构域。
14.根据声明1到12或13所述的一种方法，其中，抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括抑制至少一种异构体与内源性细胞结构或蛋白之间发生结构性相互作用。
15.根据声明1到13或14所述的一种方法，其中，抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括：(a)施用一种或多种磷脂酰肌醇-5-磷酸4-激酶异构体的抑制剂；或(b)修饰一个或多个磷脂酰肌醇-5-磷酸4-激酶基因序列。
16.根据声明1到14或15所述的一种方法，其中，抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括一种或多种抑制磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体的表达或功能。
17.根据声明16所述的一种方法，其中，抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体的表达或功能包括施用一种或多种磷脂酰肌醇-5-磷酸4-激酶异构体的抗体、核酸抑制剂或小分子抑制剂。
18.根据声明1到14或15所述的一种方法，其中，抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括使一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体接触包括SEQ ID NO:1-5或96的PIP4K肽，其中，所述PIP4K肽不是全长PIP4K多肽。
19.根据声明18所述的一种方法，其中，所述PIP4K肽不具有催化位点。
20.根据声明18所述的一种方法，其中，所述PIP4K肽的长度小于400个、小于350个、小于300个、小于250个、小于200个、小于150个或小于100个氨基酸。
21.根据声明18所述的一种方法，其中，所述PIP4K肽的长度为至少20个、至少25个、至少30个、至少35个、至少40个、至少45个或至少50个氨基酸。
22.根据声明1到20或21所述的一种方法，其中，所述一种或多种磷脂酰肌醇-5-磷酸4-激酶是PIP4K2A、PIP4K2B或PIP4K2C。
23.根据声明1到21或22所述的一种方法，其中，所述磷脂酰肌醇-5-磷酸4-激酶是PIP4K2B，并且所述受试者患有或疑似患有糖尿病、代谢综合征、胰岛素抵抗、肥胖症或其组合。
24.根据声明2到22或23所述的一种方法，其中，所述感染是细菌感染、病毒感染、真菌感染或其组合。
25.根据声明1到23或24所述的一种方法，其中，所述磷脂酰肌醇-5-磷酸4-激酶是PIP4K2C，并且所述受试者患有或疑似患有癌症、免疫缺陷、自身免疫性疾病、感染或其组合。
26.根据声明7到24或25所述的一种方法，其中，所述结合部分与一种或多种PIP4K2A、PIP4K2B或PIP4K2C蛋白特异性结合。
27.根据声明7到25或26所述的一种方法，其中，所述结合部分与表位特异性结合，所述表位的序列与SEQ ID NO:6、8或10的5个氨基酸到30个氨基酸部分具有至少95％的序列一致性。
28.根据声明7到26或27所述的一种方法，其中，所述结合部分与表位特异性结合，所述表位的序列与SEQ ID NO:1、2、3、4、5或96具有至少95％的序列一致性。
29.根据声明16到27或28所述的一种方法，其中，抑制表达或功能包括使编码一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体的核酸接触小发夹RNA、siRNA或可以表达小发夹RNA或siRNA的载体。
30.根据声明29所述的一种方法，其中，所述核酸与一种RNA结合，所述RNA与SEQID NO:7、8或11具有至少95％的序列一致性或互补性。
31.根据声明1到29或30所述的一种方法，其中，降解一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括CRISPR介导、TALENS介导或ZFN介导的敲除或敲减PIP4K2A、PIP4K2B和/或PIP4K2C。
32.根据声明31所述的一种方法，包括从所述受试者中分离细胞群以及将所述细胞与一种或多种CRISPR、TALENS或ZFN试剂一起培养产生经修饰的细胞群(包含一个或多个经修饰的磷脂酰肌醇-5-磷酸4-激酶基因序列)。
33.根据声明32所述的一种方法，其中，所述一种或多种CRISPR、TALENS或ZFN试剂包含一个或多个向导RNA或能够表达一个或多个向导RNA的载体，其中所述一个或多个向导RNA可与PIP4K2A、PIP4K2B或PIP4K2C基因组位点特异性结合。
34.一种方法，包括负调节PIP5K1A或PI3K，包括使PIP5K1A接触一种包含SEQ IDNO:1-5或96(其中X为任何氨基酸)的肽接触，其中，所述肽不是野生型磷脂酰肌醇-5-磷酸4-激酶。
35.一种方法，包括调节PIP5K1A或PI3K，包括使PIP5K1A或PI3K接触一种包含序列SEQ ID NO:1-5或96(其中X为任何氨基酸)中突变的磷脂酰肌醇-5-磷酸4-激酶。
36.根据声明34或35所述的一种方法，其中，所述肽或磷脂酰肌醇-5-磷酸4-激酶包含完整的磷脂酰肌醇-5-磷酸4-激酶催化位点。
37.一种方法，包括向受试者施用一种与内源性PIP4K或内源性PIP5K进行PIP4K相互作用的抑制剂。
38.根据声明37所述的一种方法，其中，所述抑制剂包含一个PIP4K结合部分、一种包含序列SEQ ID NO:1-5或96的PIP4K肽，或一种小分子。
39.一种试剂盒，包括一个或多个与至少一种磷脂酰肌醇-5-磷酸4-激酶特异性结合的结合部分以及用于施用所述一个或多个结合部分的说明书，其中，所述结合部分与药剂直接或间接连接，药剂向细胞发出信号降解与药剂结合的磷脂酰肌醇-5-磷酸4-激酶。
40.根据声明39所述的一种试剂盒，其中，向细胞发出信号降解与药剂结合的磷脂酰肌醇-5-磷酸4-激酶的所述药剂是E3泛素连接酶。
41.根据声明39或40所述的一种试剂盒，进一步包括向细胞发出信号降解磷脂酰肌醇-5-磷酸4-激酶的所述药剂。
42.根据声明39，40或41所述的一种试剂盒，其中，所述结合部分是一种与磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体之一特异性结合的小分子、抗体、肽、多糖或脂质。
43.根据声明39到41或42所述的一种试剂盒，其中，所述结合部分通过氢键合、疏水相互作用、空间相互作用、亲水相互作用或其组合与药剂间接连接。
44.根据声明39到42或43所述的一种试剂盒，其中，间接连接指所述结合部分与药剂之间的相互作用发生在所述结合部分与磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体之一接触之前。
45.根据声明39到43或44所述的一种试剂盒，其中，间接连接指所述结合部分与药剂之间的相互作用发生在所述结合部分与磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体之一接触之后。
46.根据声明39到44或45所述的一种试剂盒，其中，降解一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括使一种或多种异构体接触对磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体之一具有特异性的抗体，其中，所述抗体具有一种可以结合E3泛素连接酶的Fc结构域。
47.一种试剂盒，包括以下组成部分：一个或多个用于从受试者中分离细胞的无菌器具、用于培养细胞的试剂、一个或多个用于靶向一个或多个基因组PIP4K位点的向导RNA、用于将经修饰的细胞施用回受试者的器具及其任何组合。
48.根据声明47所述的一种试剂盒，进一步包括用于使用所述组成部分修饰基因组PIP4K位点并且由此抑制受试者PIP4K活性的说明书。
49.一种方法，包括在哺乳动物细胞群中敲减或敲除一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)来产生经修饰的哺乳动物细胞群(一种或多种磷脂酰肌醇-5-磷酸4-激酶的表达或功能降低)。
50.根据声明49所述的一种方法，其中，所述一种或多种磷脂酰肌醇-5-磷酸4-激酶是PIP4K2A、PIP4K2B或PIP4K2C。
51.根据声明49或50所述的一种方法，包括在述哺乳动物细胞群中敲除一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)。
52.根据声明49、50或51所述的一种方法，进一步包括向受试者施用所述经修饰的哺乳动物细胞群。
53.根据声明52所述的一种方法，其中，所述经修饰的哺乳动物细胞群可以是受试者异体的，也可以是受试者自体的。
本文所述的具体方法和组合物表示优选实施例和示例性实施例，并非旨在限制本发明的范围。一旦考虑本说明书，本领域技术人员将容易想到其它目的、方面和实施例，并且其它目的、方面和实施例属于权利要求所限定的本发明精神范围内。对于本领域的技术人员而言显而易见的是，在不脱离本发明的范围和精神的情况下，可以对本文公开的本发明做出各种替代和修改。
在不存在本文未具体公开为必要的任何一个或多个要素或一个或多个限制的情况下，可以适当地实践本文以说明性方式描述的本发明。在本文中适当以说明性方式描述的方法和过程可以按照不同的步骤顺序实施，并且所述方法和过程不必限于本文或权利要求中所示的步骤顺序。
除非上下文另有说明，本文和所附权利要求中使用的单数形式“一个/一种(a、an)”和“所述”包含复数指代物。因此，例如，对“核酸”或“蛋白质”或“细胞”的引用包含了多种此类核酸、蛋白质或细胞(例如，核酸或表达盒的溶液或干燥制剂、蛋白质溶液或细胞群)等等。在本文档中，除非另有指示，否则术语“或”用于指代非排他性，或使“A或B”包含“A但非B”、“B但非A”和“A和B”。
在任何情况下，本专利均不得解释为限于本文具体公开的具体实例或实施例或方法。在任何情况下，本专利均不得解释为受限于专利商标局的任何审查员或任何其它官员或雇员的声明，除非这类声明具体且无条件或限制地明确用于申请人的答复意见。
已采用的术语和表达用作描述性而非限制性的术语，并且不旨在使用此类术语和表达来排除所示和所述特征的任何等效物或其部分，但是应认识到，在要求保护的本发明范围内，可以做出各种修改。因此，应当理解，尽管已经通过优选实施例和任选特征具体公开了本发明，但是本领域技术人员可以对本文公开的概念进行修改和变更，并且此类修改和变更被认为是在所附权利要求和本发明的声明限定的本发明范围内。
本文宽泛且概括性地描述了本发明。一般性公开内容范围内的每个较窄种类和亚属分类也构成了本发明的一部分。其中包含本发明的一般性描述，其前提条件或负面限制从所述属中删除任何主题，无论所删除的材料是否在本文中具体叙述。另外，在根据马库什(Markush)基团描述本发明的特征或各个方面的情况下，本领域技术人员将认识到，也可由此根据马库什基团的任何单个成员或成员子组对本发明进行描述。
序列表
<110> L·C·坎特利
M·N·帕多克
D·G·王
<120> PIP4K通过非催化依赖性机制抑制胰岛素信号传导并增强免疫功能
<130> 1676.146WO1
<150> US 62/831,895
<151> 2019-04-10
<150> US 62/847,411
<151> 2019-05-14
<160> 96
<170> Windows FastSEQ版本4.0
<210> 1
<211> 26
<212> PRT
<213> 智人（Homo sapiens）
<400> 1
Ile Asn Glu Leu Ser His Val Gln Ile Pro Val Met Leu Met Pro Asp
1 5 10 15
Asp Phe Lys Ala Tyr Ser Lys Ile Lys Val
20 25
<210> 2
<211> 26
<212> PRT
<213> 智人（Homo sapiens）
<400> 2
Ile Asn Glu Leu Ser Asn Val Pro Val Pro Val Met Leu Met Pro Asp
1 5 10 15
Asp Phe Lys Ala Tyr Ser Lys Ile Lys Val
20 25
<210> 3
<211> 26
<212> PRT
<213> 智人（Homo sapiens）
<400> 3
Ile Asn Glu Leu Ser Gln Val Pro Pro Pro Val Met Leu Leu Pro Asp
1 5 10 15
Asp Phe Lys Ala Ser Ser Lys Ile Lys Val
20 25
<210> 4
<211> 26
<212> PRT
<213> 智人（Homo sapiens）
<400> 4
Ile Asn Glu Leu Ser Gln Val Pro Pro Pro Glu Ile Phe Leu Pro Asn
1 5 10 15
Asn Phe Lys Ala Ser Ser Lys Ile Lys Val
20 25
<210> 5
<211> 7
<212> PRT
<213> 智人（Homo sapiens）
<220>
<221> SITE
<222> 4
<223> Xaa = 任何氨基酸
<400> 5
Val Met Leu Xaa Pro Asp Asp
1 5
<210> 6
<211> 406
<212> PRT
<213> 智人（Homo sapiens）
<400> 6
Met Ala Thr Pro Gly Asn Leu Gly Ser Ser Val Leu Ala Ser Lys Thr
1 5 10 15
Lys Thr Lys Lys Lys His Phe Val Ala Gln Lys Val Lys Leu Phe Arg
20 25 30
Ala Ser Asp Pro Leu Leu Ser Val Leu Met Trp Gly Val Asn His Ser
35 40 45
Ile Asn Glu Leu Ser His Val Gln Ile Pro Val Met Leu Met Pro Asp
50 55 60
Asp Phe Lys Ala Tyr Ser Lys Ile Lys Val Asp Asn His Leu Phe Asn
65 70 75 80
Lys Glu Asn Met Pro Ser His Phe Lys Phe Lys Glu Tyr Cys Pro Met
85 90 95
Val Phe Arg Asn Leu Arg Glu Arg Phe Gly Ile Asp Asp Gln Asp Phe
100 105 110
Gln Asn Ser Leu Thr Arg Ser Ala Pro Leu Pro Asn Asp Ser Gln Ala
115 120 125
Arg Ser Gly Ala Arg Phe His Thr Ser Tyr Asp Lys Arg Tyr Ile Ile
130 135 140
Lys Thr Ile Thr Ser Glu Asp Val Ala Glu Met His Asn Ile Leu Lys
145 150 155 160
Lys Tyr His Gln Tyr Ile Val Glu Cys His Gly Ile Thr Leu Leu Pro
165 170 175
Gln Phe Leu Gly Met Tyr Arg Leu Asn Val Asp Gly Val Glu Ile Tyr
180 185 190
Val Ile Val Thr Arg Asn Val Phe Ser His Arg Leu Ser Val Tyr Arg
195 200 205
Lys Tyr Asp Leu Lys Gly Ser Thr Val Ala Arg Glu Ala Ser Asp Lys
210 215 220
Glu Lys Ala Lys Glu Leu Pro Thr Leu Lys Asp Asn Asp Phe Ile Asn
225 230 235 240
Glu Gly Gln Lys Ile Tyr Ile Asp Asp Asn Asn Lys Lys Val Phe Leu
245 250 255
Glu Lys Leu Lys Lys Asp Val Glu Phe Leu Ala Gln Leu Lys Leu Met
260 265 270
Asp Tyr Ser Leu Leu Val Gly Ile His Asp Val Glu Arg Ala Glu Gln
275 280 285
Glu Glu Val Glu Cys Glu Glu Asn Asp Gly Glu Glu Glu Gly Glu Ser
290 295 300
Asp Gly Thr His Pro Val Gly Thr Pro Pro Asp Ser Pro Gly Asn Thr
305 310 315 320
Leu Asn Ser Ser Pro Pro Leu Ala Pro Gly Glu Phe Asp Pro Asn Ile
325 330 335
Asp Val Tyr Gly Ile Lys Cys His Glu Asn Ser Pro Arg Lys Glu Val
340 345 350
Tyr Phe Met Ala Ile Ile Asp Ile Leu Thr His Tyr Asp Ala Lys Lys
355 360 365
Lys Ala Ala His Ala Ala Lys Thr Val Lys His Gly Ala Gly Ala Glu
370 375 380
Ile Ser Thr Val Asn Pro Glu Gln Tyr Ser Lys Arg Phe Leu Asp Phe
385 390 395 400
Ile Gly His Ile Leu Thr
405
<210> 7
<211> 3820
<212> DNA
<213> 智人（Homo sapiens）
<400> 7
agccgcgggc tgagcgcgga tccgcggcgg gcgcaggata cgggccgggg cgcgagccga 60
gcgcagtctg ccgggccgag cgggcggagc gagccgagtg gggctgagcg cgccggcggc 120
ggcgggcgga gcggagcgcg gcgcgccggg gccgccgccg gggggatgcg gctgcctccc 180
cgggccgggg tgtagagagg gcgggtcccc ggcctcggga gcacggcggt ggaggggaca 240
taggaggcgg ccatggcgac ccccggcaac ctagggtcct ctgtcctggc gagcaagacc 300
aagaccaaga agaagcactt cgtagcgcag aaagtgaagc tgtttcgggc cagcgacccg 360
ctgctcagcg tcctcatgtg gggggtaaac cactcgatca atgaactgag ccatgttcaa 420
atccctgtta tgttgatgcc agatgacttc aaagcctatt caaaaataaa ggtggacaat 480
caccttttta acaaagaaaa catgccgagc catttcaagt ttaaggaata ctgcccgatg 540
gtcttccgta acctgcggga gaggtttgga attgatgatc aagatttcca gaattccctg 600
accaggagcg cacccctccc caacgactcc caggcccgca gtggagctcg ttttcacact 660
tcctacgaca aaagatacat catcaagact attaccagtg aagacgtggc cgaaatgcac 720
aacatcctga agaaatacca ccagtacata gtggaatgtc atgggatcac ccttcttccc 780
cagttcttgg gcatgtaccg gcttaatgtt gatggagttg aaatatatgt gatagttaca 840
agaaatgtat tcagccaccg tttgtctgtg tataggaaat acgacttaaa gggctctaca 900
gtggctagag aagctagtga caaagaaaag gccaaagaac tgccaactct gaaagataat 960
gatttcatta atgagggcca aaagatttat attgatgaca acaacaagaa ggtcttcctg 1020
gaaaaactaa aaaaggatgt tgagtttctg gcccagctga agctcatgga ctacagtctg 1080
ctggtgggaa ttcatgatgt ggagagagcc gaacaggagg aagtggagtg tgaggagaac 1140
gatggggagg aggagggcga gagcgatggc acccacccgg tgggaacccc cccagatagc 1200
cccgggaata cactgaacag ctcaccaccc ctggctcccg gggagttcga tccgaacatc 1260
gacgtctatg gaattaagtg ccatgaaaac tcgcctagga aggaggtgta cttcatggca 1320
attattgaca tccttactca ttatgatgca aaaaagaaag ctgcccatgc tgcaaaaact 1380
gttaaacatg gcgctggcgc ggagatctcc accgtgaacc cagaacagta ttcaaagcgc 1440
tttttggact ttattggcca catcttgacg taacctcctg cgcagcctcg gacagacatg 1500
aacattggat ggacagaggt ggcttcggtg taggaaaaat gaaaaccaaa ctcagtgaag 1560
tactcatctt gcaggaagca aacctccttg tttacatctt caggccaaga tgactgattt 1620
gggggctact cgctttacag ctacctgatt ttcccagcat cgttctagct atttctgact 1680
ttgtgtatat gtgtgtgtgt gtgtgttggg ggggggtgag tgtgtgcgcg cgtgtgcatt 1740
ttaaaagtca taaattaatt aaaacagatc cacttcggtc agtatgtgtc ccaacaaaga 1800
ccctttgatt ccagctatgg ccgaatgaat gagtgagtga gtgagtgagt gaatgaacac 1860
acgtgtgggg gaggggagaa ggaagtgcat gatgtcaggc accgtgttgg catcacacaa 1920
caaactgtgg atcagttttt tttttttttt tttttttttg gagttgaaag atgtgagaca 1980
gtattcagaa taatgaagat aataatgatg attattataa taatgatgat gattccaagg 2040
aaaaaaccta cagcgaatgt tccatttcta ccccgcacgc agacactctc cctaacactg 2100
ataacctgag cccccagcac tggacggaag aatgctggcg tctccgtgtg tactggttca 2160
gggttctggc cccagccttg tcaggacccc ctggtgtcca gagcccccac ccctcccgca 2220
acaagcagct gatgccccag tgattctcta tacatttttc acctcggcca atatgtccag 2280
gaaaactgct tacttctctt ttcttgcctg gagccttcat tgttcaccct tacgttgcaa 2340
tataggaatt aatgctacaa aataaaagta aagcttacct gaaaagtgca tagtttgggg 2400
caatggtatc tacatctccc actgtgggaa aaccagcaaa gcatcaaaac tctcaattct 2460
cctgttacca aatgcagatc tgaattataa gatgtttatg tttgaccatt gtttcaacaa 2520
tgggattttg ttacgaatta tccctttaac tgaaaccctc agttttactg tttacattat 2580
taggaaaaca gggatatctt ttgaatctaa aaatttgatg tacagcatgt gatttttgaa 2640
gtttacatgt aaagtcacag tataggtgaa ataacgtttg tcatattttg agacgtatcc 2700
tgcagccatg tttttacgtg agtgttttag tcaaagtaca tggtagacag tctttcacaa 2760
taaaaggaaa aggatttttt tttcctccaa atgtacattt atcaacctaa tgattgattt 2820
ttttaaaaag agatttcgcc ccagtctggt ttatgaaagt tcattgccct aaactgtgct 2880
gattgttttt aatcaagtta taaatttcca acctagatca tgtatctacc aactctcctg 2940
cattttccaa aaggcattga gcttaaatat tagtcttgct tagagtaggt tatccactta 3000
catgctgcgc taaagccatg cctttgaaac tccttgttta aaacatgata tgatttttgt 3060
gggcagtttc agaaaagaaa acaaacaaac aaaaatcgac cctttaatta ttacttgcaa 3120
ctcaacagat ctccctgccg tactgccttt tccaggaact ttacttcagg gctgtccaga 3180
ttgcagctgt gccccgtgta tgtggatcta gttcacagag tctttggaag ccagcagtcg 3240
tgccctccgt atactgtcca ctcattttat gtagatttgg tatcctcagc agccagtgtt 3300
aacaccactg tcacgtagtg tacagattca tcttttatgt atttaaagta atccatacta 3360
tgatttggtt tttccctgca ccattaattc tggcatcaga tcagtttttg tgttgtgaag 3420
ttctactgtg gtttgaccca agaccacaac catgagaccc tgaagtaaag ataaggtaca 3480
catacattat ttgagtaact gtttccttgg gggccaatct gtgtatgctt ttagaagttt 3540
acagaatgct tttatttttg tctataacaa acagtctgtc atttatttct gttgataaac 3600
catttggaca gagtgaggac gtttgccctg ttatctccta gtgctaacaa tacactccag 3660
tcatgagccg ggctttacaa ataaagcact tttgatgact cacaagatga atcctttttt 3720
cctctgtccc aattgtgtgt ctctgttcca aacacatttt aaatactcgg tcctgacagt 3780
gtctttagct aatccttgaa gaaatgaaag tggaattgaa 3820
<210> 8
<211> 416
<212> PRT
<213> 智人（Homo sapiens）
<400> 8
Met Ser Ser Asn Cys Thr Ser Thr Thr Ala Val Ala Val Ala Pro Leu
1 5 10 15
Ser Ala Ser Lys Thr Lys Thr Lys Lys Lys His Phe Val Cys Gln Lys
20 25 30
Val Lys Leu Phe Arg Ala Ser Glu Pro Ile Leu Ser Val Leu Met Trp
35 40 45
Gly Val Asn His Thr Ile Asn Glu Leu Ser Asn Val Pro Val Pro Val
50 55 60
Met Leu Met Pro Asp Asp Phe Lys Ala Tyr Ser Lys Ile Lys Val Asp
65 70 75 80
Asn His Leu Phe Asn Lys Glu Asn Leu Pro Ser Arg Phe Lys Phe Lys
85 90 95
Glu Tyr Cys Pro Met Val Phe Arg Asn Leu Arg Glu Arg Phe Gly Ile
100 105 110
Asp Asp Gln Asp Tyr Gln Asn Ser Val Thr Arg Ser Ala Pro Ile Asn
115 120 125
Ser Asp Ser Gln Gly Arg Cys Gly Thr Arg Phe Leu Thr Thr Tyr Asp
130 135 140
Arg Arg Phe Val Ile Lys Thr Val Ser Ser Glu Asp Val Ala Glu Met
145 150 155 160
His Asn Ile Leu Lys Lys Tyr His Gln Phe Ile Val Glu Cys His Gly
165 170 175
Asn Thr Leu Leu Pro Gln Phe Leu Gly Met Tyr Arg Leu Thr Val Asp
180 185 190
Gly Val Glu Thr Tyr Met Val Val Thr Arg Asn Val Phe Ser His Arg
195 200 205
Leu Thr Val His Arg Lys Tyr Asp Leu Lys Gly Ser Thr Val Ala Arg
210 215 220
Glu Ala Ser Asp Lys Glu Lys Ala Lys Asp Leu Pro Thr Phe Lys Asp
225 230 235 240
Asn Asp Phe Leu Asn Glu Gly Gln Lys Leu His Val Gly Glu Glu Ser
245 250 255
Lys Lys Asn Phe Leu Glu Lys Leu Lys Arg Asp Val Glu Phe Leu Ala
260 265 270
Gln Leu Lys Ile Met Asp Tyr Ser Leu Leu Val Gly Ile His Asp Val
275 280 285
Asp Arg Ala Glu Gln Glu Glu Met Glu Val Glu Glu Arg Ala Glu Asp
290 295 300
Glu Glu Cys Glu Asn Asp Gly Val Gly Gly Asn Leu Leu Cys Ser Tyr
305 310 315 320
Gly Thr Pro Pro Asp Ser Pro Gly Asn Leu Leu Ser Phe Pro Arg Phe
325 330 335
Phe Gly Pro Gly Glu Phe Asp Pro Ser Val Asp Val Tyr Ala Met Lys
340 345 350
Ser His Glu Ser Ser Pro Lys Lys Glu Val Tyr Phe Met Ala Ile Ile
355 360 365
Asp Ile Leu Thr Pro Tyr Asp Thr Lys Lys Lys Ala Ala His Ala Ala
370 375 380
Lys Thr Val Lys His Gly Ala Gly Ala Glu Ile Ser Thr Val Asn Pro
385 390 395 400
Glu Gln Tyr Ser Lys Arg Phe Asn Glu Phe Met Ser Asn Ile Leu Thr
405 410 415
<210> 9
<211> 5732
<212> DNA
<213> 智人（Homo sapiens）
<400> 9
ttgcgggaaa gagccaaacc ctggcgttgg ggggcccggg cggggagccc ctcccgcggt 60
ccacagcgac gcctgcccag ccctcctccc cttccggctc cggcacgggg ccccgaggcg 120
ttcggaggcc aggcgggttt ctgtcaggcc cggggaggag gggcgggcgg ggcggccgct 180
gcctccccgg gacgggccgt accacgcgga cggggaggac ggggccaggg gactgcaggg 240
cggctgcacc gcccgggggc ggggtgcgga gcgggccggc gggctccccg gggcggggcg 300
ggagggcggg gcgtggggcg gacggaacca ccggggcggg gtgggaggta acgggacggg 360
cgcgaccatg gcgcggtgag ggagcggggg tggggatcgg tccgggggag gcctgaggcc 420
gctggcttgt gcgctgtctc cgccgccccc ctctttcgcc gccgccgccg ccgccccggg 480
catgtcgtcc aactgcacca gcaccacggc ggtggcggtg gcgccgctca gcgccagcaa 540
gaccaagacc aagaagaagc atttcgtgtg ccagaaagtg aagctattcc gggccagcga 600
gccgatcctc agcgtcctga tgtggggggt gaaccacacg atcaatgagc tgagcaatgt 660
tcctgttcct gtcatgctaa tgccagatga cttcaaagcc tacagcaaga tcaaggtgga 720
caatcatctc ttcaataagg agaacctgcc cagccgcttt aagtttaagg agtattgccc 780
catggtgttc cgaaaccttc gggagaggtt tggaattgat gatcaggatt accagaattc 840
agtgacgcgc agcgccccca tcaacagtga cagccagggt cggtgtggca cgcgtttcct 900
caccacctac gaccggcgct ttgtcatcaa gactgtgtcc agcgaggacg tggcggagat 960
gcacaacatc ttaaagaaat accaccagtt tatagtggag tgtcatggca acacgctttt 1020
gccacagttc ctgggcatgt accgcctgac cgtggatggt gtggaaacct acatggtggt 1080
taccaggaac gtgttcagcc atcggctcac tgtgcatcgc aagtatgacc tcaagggttc 1140
tacggttgcc agagaagcga gcgacaagga gaaggccaag gacttgccaa cattcaaaga 1200
caatgacttc ctcaatgaag ggcagaagct gcatgtggga gaggagagta aaaagaactt 1260
cctggagaaa ctgaagcggg acgttgagtt cttggcacag ctgaagatca tggactacag 1320
cctgctggtg ggcatccacg acgtggaccg ggcagagcag gaggagatgg aggtggagga 1380
gcgggcagag gacgaggagt gtgagaatga tggggtgggt ggcaacctac tctgctccta 1440
tggcacacct ccggacagcc ctggcaacct cctcagcttt cctcggttct ttggtcctgg 1500
ggaattcgac ccctctgttg acgtctatgc catgaaaagc catgaaagtt cccccaagaa 1560
ggaggtgtat ttcatggcca tcattgatat cctcacgcca tacgatacaa agaagaaagc 1620
tgcacatgct gccaaaacgg tgaaacacgg ggcaggggcc gagatctcga ctgtgaaccc 1680
tgagcagtac tccaaacgct tcaacgagtt tatgtccaac atcctgacgt agttctcttc 1740
taccttcagc cagagccaga gagctggata tggggtcggg gatcgggagt tagggagaag 1800
ggtgtatttg ggctagatgg gagggtggga gcagagtcgg gtttgggagg gctttagcaa 1860
tgagactgca gcctgtgaca ccgaaagaga ctttagctga agaggagggg gatgtgctgt 1920
gtgtgcacct gctcacagga tgtaacccca ccttctgctt acccttgatt ttttctcccc 1980
atttgacacc caggttaaaa aggggttccc tttttggtac cttgtaacct tttaagatac 2040
cttggggcta gagatgactt cgtgggttta tttgggtttt gtttctgaaa tttcattgct 2100
ccaggtttgc tatttataat catatttcat cagcctaccc accctcccca tctttgctga 2160
gctctcagtt cccttcaatt aaagagatac ccggtagacc cagcacaagg gtccttccag 2220
aaccaagtgc tatggatgcc agattggaga ggtcagacac ctcgccctgc tgcatttgct 2280
cttgtctgga ttaactttgt aatttatgga gtattgtgca caacttcctc cacctttccc 2340
ttggattcaa gtgaaaactg ttgcattatt cctccatcct gtctggaata caccaggtca 2400
acaccagaga tctcagatca gaatcagaga tctcagaggg gaataagttc atcctcatgg 2460
gatggtgagg ggcaggaaag cggctgggct cttggacacc tggttctcag agaaccctgt 2520
gatgatcacc caagccccag gctgtcttag cccctggagt tcagaagtcc tctctgtaaa 2580
gcctgcctcc cactaggtca agaggaacta gagtaccttt ggatttatca ggaccctcat 2640
gtttaaatgg ttatttccct ttgggaaaac ttcagaaact gatgtatcaa atgaggccct 2700
gtgccctcga tctatttcct tcttccttct gacctcctcc caggcactct tacttctagc 2760
cgaactctta gctctgggca gatctccaag cgcctggagt gctttttagc agagacacct 2820
cgttaagctc cgggatgacc ttgtaggaga tctgtctccc tgtgcctgga gagttacagc 2880
cagcaaggtg cccccatctt agagtgtggt gtccaaacgt gaggtggctt cctagttaca 2940
tgaggatgtg atccaggaaa tccagtttgg aggcttgatg tgggttttga cctggcctca 3000
gccttggggc tgtttttcct tgttgccccg ctctagactt ttagcagatc tgcagcccac 3060
aggctttttt ggaaggagtg gcttcctgca ggtgttccac ctgccttcgg agcctgccac 3120
ccaggccctc agaactgagc cacaggctgc tctggccagg agagaaacag ctctgttgtt 3180
ctgcattggg ggaggtacat tcctgcatct tctcaccccc tcaaccagga actggggatt 3240
tgggatgaga tatggtcaga cttgtagata accccaaaga tgtgaagatc gcttgtgaaa 3300
ccattttgaa tgaatagatt ggtttcctgt ggctccctcc aaacctggcc aagcccagct 3360
tccgaagcag gaaccagcac tgtctctgtg cctgactcac agcatatagg tcaggaaaga 3420
atggagacgg cattcttgga cttcactggg gctgctggat tggatgggaa accttctgga 3480
agaggcagat gggggtcaaa ccactgcctt ggccccagga aggggccata ggtaggtctg 3540
aacaactgcc gcaagaccac tacatgactt agggaacttg aaaccaactg gctcatggag 3600
aaaacaaatt tgacttggga aagggattat gtaggaataa tgtttggact tgatttcccc 3660
acgtcataat gaagaatgga agtttggatc tgctcctcgt caggcgcagc atctctgaag 3720
cttggaaagc tgtcttccag cagcctccgt ggcctcgggt tcctaccggc ttctctgcat 3780
ttggtctgct gatcatgttg ccataatgtg tatggaaagt gtaacacatt cttactggtt 3840
aaagacgact accaggtatc taacttgttt aacattgagt ttgtgtgtgt gtgtgtatgt 3900
ttgtgtgttt tgtatattgt ttacattttg agaggtagca ttctgtttca aatgcttttt 3960
gtttttctga cagtattgtt gactgggtca taacattttg agctgtggtt tggtggattt 4020
tcaatttttt tttttaaagg tcattcgctg tgctatcttc aaaaccttga gtttggcccc 4080
caatttttgg cattcaaatg tttaaaagct atttatcttg gtttatacaa gtttcctttc 4140
tcttcttttt gtcatggtat tctatttggt ctgcagtttg aatgtagaga aagtggactg 4200
atcccccaag cgttgtctgc ccccactctt tcctccttgg gtcccgccat tcttttactg 4260
ggcagtcgag ggcattggag gggaagtgac tgccctcagc ctcactccct ggggccatga 4320
agaaaagcta aacagtctca tggcatctca gaataatgtt gggtctccca agaagaaagg 4380
tgtaagaata acgacatggc tgattaggcg aggccaggat agggctaagg ccaggattcc 4440
tggctggcat ccagtcaccc cttctcccat ccttccccct cttcttccac aagtccgcag 4500
ccgagacact gtagtctccc agccacagtg atgagtgccc tggagactcc actgacctct 4560
agatgaaggc ccctggccct ggttcctgtt aattaacctc tgggtctttg agtcccccag 4620
cacaaacttc tttcctgtac cctgcggctt ggggtcacag ggcatgccgg gaagccacag 4680
ctgaggggcg cagactgaag cagtgctcca cctctccttc tttagctcag gggttgctgg 4740
tctgtggcag gcgccacgag tggcccctgt ggctgttctc agtggcagtc tcttaagttc 4800
ccaccacagg cagctcttta tcccctctcc ctacttgact ctttctcttg cctgtgcttt 4860
tggcctcaaa caggcctgct ggtagcgctc agggcgtgag gctacactcc tgccctgcct 4920
ttcctgtctt catggtctgc cagggcatac cttggggagg tggaccaaag acccaggact 4980
ttttgcagta gccagtccta ccccccagtt gtctttttac caattcaggg tgggagagaa 5040
aactgcagca ccccagcatg tgagttactc aggtgttggg ggctagaagg gacagtgcgt 5100
ttaaacaaca ctcagagctc tggccttaaa cctgtggccc cccaagtcta ggagcctcat 5160
ctcttcctgg cagtcatgcg ggcaggaggt cctgaaaggg aaaacccatt cagacaactg 5220
ttccccaatc taccagccat ctgcaggggt cagtgaccgt ggccctctcc ctcctctaga 5280
atgtgccact tatgaagagt gccccatggg gaaaaggaga ctcagctgtc ccttggcagc 5340
ttgtgccagt atcccagggc agaagtttcc acaggagcct cttgcccttg cgcagagcca 5400
ctgtgagagg cggtgggagc caacaccctt gggggagggg gcagtactgc tcggcacatc 5460
ccagcatcag gtcagatcat tgaaattaaa aaatgtgaat taagttcata tccacctttt 5520
ggggaagcag gacaaaccac caccccacca agtgtgtgac ttctccatat cccactgcag 5580
tttccatttt ttaaatggga attttcaatc ccctgtgctt gtctaacgtc tgctttaaaa 5640
agtttgagac cctgttactg tttgaaaatg catgcatgtt acgatgaatc tccaacctga 5700
ggaaaaaaat aaaactcaaa aagctttgtg ta 5732
<210> 10
<211> 421
<212> PRT
<213> 智人（Homo sapiens）
<400> 10
Met Ala Ser Ser Ser Val Pro Pro Ala Thr Val Ser Ala Ala Thr Ala
1 5 10 15
Gly Pro Gly Pro Gly Phe Gly Phe Ala Ser Lys Thr Lys Lys Lys His
20 25 30
Phe Val Gln Gln Lys Val Lys Val Phe Arg Ala Ala Asp Pro Leu Val
35 40 45
Gly Val Phe Leu Trp Gly Val Ala His Ser Ile Asn Glu Leu Ser Gln
50 55 60
Val Pro Pro Pro Val Met Leu Leu Pro Asp Asp Phe Lys Ala Ser Ser
65 70 75 80
Lys Ile Lys Val Asn Asn His Leu Phe His Arg Glu Asn Leu Pro Ser
85 90 95
His Phe Lys Phe Lys Glu Tyr Cys Pro Gln Val Phe Arg Asn Leu Arg
100 105 110
Asp Arg Phe Gly Ile Asp Asp Gln Asp Tyr Leu Val Ser Leu Thr Arg
115 120 125
Asn Pro Pro Ser Glu Ser Glu Gly Ser Asp Gly Arg Phe Leu Ile Ser
130 135 140
Tyr Asp Arg Thr Leu Val Ile Lys Glu Val Ser Ser Glu Asp Ile Ala
145 150 155 160
Asp Met His Ser Asn Leu Ser Asn Tyr His Gln Tyr Ile Val Lys Cys
165 170 175
His Gly Asn Thr Leu Leu Pro Gln Phe Leu Gly Met Tyr Arg Val Ser
180 185 190
Val Asp Asn Glu Asp Ser Tyr Met Leu Val Met Arg Asn Met Phe Ser
195 200 205
His Arg Leu Pro Val His Arg Lys Tyr Asp Leu Lys Gly Ser Leu Val
210 215 220
Ser Arg Glu Ala Ser Asp Lys Glu Lys Val Lys Glu Leu Pro Thr Leu
225 230 235 240
Lys Asp Met Asp Phe Leu Asn Lys Asn Gln Lys Val Tyr Ile Gly Glu
245 250 255
Glu Glu Lys Lys Ile Phe Leu Glu Lys Leu Lys Arg Asp Val Glu Phe
260 265 270
Leu Val Gln Leu Lys Ile Met Asp Tyr Ser Leu Leu Leu Gly Ile His
275 280 285
Asp Ile Ile Arg Gly Ser Glu Pro Glu Glu Glu Ala Pro Val Arg Glu
290 295 300
Asp Glu Ser Glu Val Asp Gly Asp Cys Ser Leu Thr Gly Pro Pro Ala
305 310 315 320
Leu Val Gly Ser Tyr Gly Thr Ser Pro Glu Gly Ile Gly Gly Tyr Ile
325 330 335
His Ser His Arg Pro Leu Gly Pro Gly Glu Phe Glu Ser Phe Ile Asp
340 345 350
Val Tyr Ala Ile Arg Ser Ala Glu Gly Ala Pro Gln Lys Glu Val Tyr
355 360 365
Phe Met Gly Leu Ile Asp Ile Leu Thr Gln Tyr Asp Ala Lys Lys Lys
370 375 380
Ala Ala His Ala Ala Lys Thr Val Lys His Gly Ala Gly Ala Glu Ile
385 390 395 400
Ser Thr Val His Pro Glu Gln Tyr Ala Lys Arg Phe Leu Asp Phe Ile
405 410 415
Thr Asn Ile Phe Ala
420
<210> 11
<211> 3176
<212> DNA
<213> 智人（Homo sapiens）
<400> 11
ggtcacgtga cagcagcgca ggtgagcgcc gcttccgggg tcgggcgcct ggatagctgc 60
cggctccggc ttccacttgg tcggttgcgc gggagactat ggcgtcctcc tcggtcccac 120
cagccacggt atcggcggcg acagcaggcc ccggcccagg tttcggcttc gcctccaaga 180
ccaagaagaa gcatttcgtg cagcagaagg tgaaggtgtt ccgggcggcc gacccgctgg 240
tgggtgtgtt cctgtggggc gtagcccact cgatcaatga gctcagccag gtgcctcccc 300
cggtgatgct gctgccagat gactttaagg ccagctccaa gatcaaggtc aacaatcacc 360
ttttccacag ggaaaatctg cccagtcatt tcaagttcaa ggagtattgt ccccaggtct 420
tcaggaacct ccgtgatcga tttggcattg atgaccaaga ttacttggtg tcccttaccc 480
gaaacccccc cagcgaaagt gaaggcagtg atggtcgctt ccttatctcc tacgatcgga 540
ctctggtcat caaagaagta tccagtgagg acattgctga catgcatagc aacctctcca 600
actatcacca gtacattgtg aagtgccatg gcaacacgct tctgccccag ttcctgggga 660
tgtaccgagt cagtgtggac aacgaagaca gctacatgct tgtgatgcgc aatatgttta 720
gccaccgtct tcctgtgcac aggaagtatg acctcaaggg ttccctagtg tcccgggaag 780
ccagcgataa ggaaaaggtt aaagaattgc ccacccttaa ggatatggac tttctcaaca 840
agaaccagaa agtatatatt ggtgaagagg agaagaaaat atttctggag aagctgaaga 900
gagatgtgga gtttctagtg cagctgaaga tcatggacta cagccttctg ctaggcatcc 960
acgacatcat tcggggctct gaaccagagg aggaagcgcc cgtgcgggag gatgagtcag 1020
aggtggatgg ggactgcagc ctgactggac ctcctgctct ggtgggctcc tatggcacct 1080
ccccagaggg tatcggaggc tacatccatt cccatcggcc cctgggccca ggagagtttg 1140
agtccttcat tgatgtctat gccatccgga gtgctgaagg agccccccag aaggaggtct 1200
acttcatggg cctcattgat atccttacac agtatgatgc taagaagaaa gcagctcatg 1260
cagccaaaac tgtcaagcat ggggctgggg cagagatctc tactgtccat ccggagcagt 1320
atgctaagcg attcctggat tttattacca acatctttgc ctaagagact gcctggttct 1380
ctctgatgtt caaggtggtg gggttctgag acacttgggg gaattgtggg gatattctag 1440
ccaccagttc tcttcttcct ttgctaaatt caggctgcag gctccttcca tccagataac 1500
tccatcctgt cgagtaggct ctttctgacc ctcagaaata cattgtcctt tttcctcttt 1560
gcccattttt cttccctctc ttcctcccca tgagaagtct gcttgtagta ttagaatgtt 1620
attgttgact ctctcccaag tgccttgatc tttgtaatat ctcctgttgt ttctatgata 1680
taggagctag gggaaggggg ttgtttgcct tcttcaggac ctgactggac agatggacct 1740
ggctcaagca actactctgg atgcactttg ctgtgtggga tgaactaaaa gtgtctgaat 1800
tttgctgata actttataaa actcactatg gcatgcttcc ctcctggtgg gccctaggat 1860
ggatgacact caagatacta cagatgtggg tgcaggcatg cacacacacg atggaatatg 1920
gccattccta cacaggtggg gtagagagtg ggtcagcagc ctggcacctc acagaggtgg 1980
gacctaagag gactcatgat tatgcagaga attggattgg gtctctgtca tagattgagt 2040
aatctcttcc cttacctcaa ttccatctcc acccatctct acatctgggc acagcaaccc 2100
agagatggcc aaaagcattc aagcctgggg gaagatgttt gactattgct gctcttcacc 2160
agaacctcac acctctcctg ggactggaac ccttcagtgg gtgtgtggcc agttttggag 2220
gctggaatga tgggccaggg tgtaggattc attctccatg taaagtttcc tttcatcctg 2280
cctagccatc cccaaggttt atttccagaa gaaaggaata tctctacttg gatcaattct 2340
ggtcatttca agaggatgga ggcctcaagt gtgggaactt cccctactcc ctggatgtgt 2400
gtacctagca cacttccttc tcccacccct ttttccagtt ggatttgttt ttctgttctc 2460
ttctgtcctg tcttatactg caactgtgtc tcctagggga cagatggcct tctttgtcat 2520
cttcactctc cacccccaga gaggagtcag agccataact caatcactca gcccctccaa 2580
agatagttga tgtgtgataa tctcataatg ttgagaaccc tgatgagata cattgtcttc 2640
ctctccctac aatgcctctg gggccaaggc acccattctt cttgctatcc tccatccccc 2700
ttgaggcttc cacttttttt ttttttagac ataaagctgg gcatcagcaa ctggcctgtg 2760
gtgatgcaaa gctgctttgc tctgtatctg gctggactga tctgtctcac aagaagccat 2820
gaggccatag ggagaagctc cctctcccct tcatcttctg ctccaaaggt ggtagcaaga 2880
ggagtaccca gttaggggtt ggagccccca tataacatct tcctgtcaga agactgatgg 2940
atctttttca ttccaaccat ctccctttcc cccgatgaat gcaataaaac tctgtgacac 3000
cagcaaccat tgctctttag aaatgggttt tctgatcata tggctgatgt gttatgggca 3060
gtatggatgt cttcatttgt tgcttctgtt tttcatcttt tttgttttat taataaaaat 3120
ttatgtattt gctcctgtta ctataataat acagggaata aattattcaa tccaaa 3176
<210> 12
<211> 491
<212> PRT
<213> 智人（Homo sapiens）
<400> 12
Met Cys Asn Thr Asn Met Ser Val Pro Thr Asp Gly Ala Val Thr Thr
1 5 10 15
Ser Gln Ile Pro Ala Ser Glu Gln Glu Thr Leu Val Arg Pro Lys Pro
20 25 30
Leu Leu Leu Lys Leu Leu Lys Ser Val Gly Ala Gln Lys Asp Thr Tyr
35 40 45
Thr Met Lys Glu Val Leu Phe Tyr Leu Gly Gln Tyr Ile Met Thr Lys
50 55 60
Arg Leu Tyr Asp Glu Lys Gln Gln His Ile Val Tyr Cys Ser Asn Asp
65 70 75 80
Leu Leu Gly Asp Leu Phe Gly Val Pro Ser Phe Ser Val Lys Glu His
85 90 95
Arg Lys Ile Tyr Thr Met Ile Tyr Arg Asn Leu Val Val Val Asn Gln
100 105 110
Gln Glu Ser Ser Asp Ser Gly Thr Ser Val Ser Glu Asn Arg Cys His
115 120 125
Leu Glu Gly Gly Ser Asp Gln Lys Asp Leu Val Gln Glu Leu Gln Glu
130 135 140
Glu Lys Pro Ser Ser Ser His Leu Val Ser Arg Pro Ser Thr Ser Ser
145 150 155 160
Arg Arg Arg Ala Ile Ser Glu Thr Glu Glu Asn Ser Asp Glu Leu Ser
165 170 175
Gly Glu Arg Gln Arg Lys Arg His Lys Ser Asp Ser Ile Ser Leu Ser
180 185 190
Phe Asp Glu Ser Leu Ala Leu Cys Val Ile Arg Glu Ile Cys Cys Glu
195 200 205
Arg Ser Ser Ser Ser Glu Ser Thr Gly Thr Pro Ser Asn Pro Asp Leu
210 215 220
Asp Ala Gly Val Ser Glu His Ser Gly Asp Trp Leu Asp Gln Asp Ser
225 230 235 240
Val Ser Asp Gln Phe Ser Val Glu Phe Glu Val Glu Ser Leu Asp Ser
245 250 255
Glu Asp Tyr Ser Leu Ser Glu Glu Gly Gln Glu Leu Ser Asp Glu Asp
260 265 270
Asp Glu Val Tyr Gln Val Thr Val Tyr Gln Ala Gly Glu Ser Asp Thr
275 280 285
Asp Ser Phe Glu Glu Asp Pro Glu Ile Ser Leu Ala Asp Tyr Trp Lys
290 295 300
Cys Thr Ser Cys Asn Glu Met Asn Pro Pro Leu Pro Ser His Cys Asn
305 310 315 320
Arg Cys Trp Ala Leu Arg Glu Asn Trp Leu Pro Glu Asp Lys Gly Lys
325 330 335
Asp Lys Gly Glu Ile Ser Glu Lys Ala Lys Leu Glu Asn Ser Thr Gln
340 345 350
Ala Glu Glu Gly Phe Asp Val Pro Asp Cys Lys Lys Thr Ile Val Asn
355 360 365
Asp Ser Arg Glu Ser Cys Val Glu Glu Asn Asp Asp Lys Ile Thr Gln
370 375 380
Ala Ser Gln Ser Gln Glu Ser Glu Asp Tyr Ser Gln Pro Ser Thr Ser
385 390 395 400
Ser Ser Ile Ile Tyr Ser Ser Gln Glu Asp Val Lys Glu Phe Glu Arg
405 410 415
Glu Glu Thr Gln Asp Lys Glu Glu Ser Val Glu Ser Ser Leu Pro Leu
420 425 430
Asn Ala Ile Glu Pro Cys Val Ile Cys Gln Gly Arg Pro Lys Asn Gly
435 440 445
Cys Ile Val His Gly Lys Thr Gly His Leu Met Ala Cys Phe Thr Cys
450 455 460
Ala Lys Lys Leu Lys Lys Arg Asn Lys Pro Cys Pro Val Cys Arg Gln
465 470 475 480
Pro Ile Gln Met Ile Val Leu Thr Tyr Phe Pro
485 490
<210> 13
<211> 64
<212> PRT
<213> 智人（Homo sapiens）
<400> 13
Met Cys Asn Thr Asn Met Ser Val Pro Thr Asp Gly Ala Val Thr Thr
1 5 10 15
Ser Gln Ile Pro Ala Ser Glu Gln Glu Thr Leu Val Arg Pro Lys Pro
20 25 30
Leu Leu Leu Lys Leu Leu Lys Ser Val Gly Ala Gln Lys Asp Thr Tyr
35 40 45
Thr Met Lys Glu Phe Ala Thr Lys His Arg Ala Lys Asn Ile Pro Val
50 55 60
<210> 14
<211> 60
<212> PRT
<213> 智人（Homo sapiens）
<400> 14
Met Cys Asn Thr Asn Met Ser Val Pro Thr Asp Gly Ala Val Thr Thr
1 5 10 15
Ser Gln Ile Pro Ala Ser Glu Gln Glu Thr Leu Val Arg Pro Lys Pro
20 25 30
Leu Leu Leu Lys Leu Leu Lys Ser Val Gly Ala Gln Lys Asp Thr Tyr
35 40 45
Thr Met Lys Glu Asn His Arg Thr Gln Val His Leu
50 55 60
<210> 15
<211> 73
<212> PRT
<213> 智人（Homo sapiens）
<400> 15
Met Cys Asn Thr Asn Met Ser Val Pro Thr Asp Gly Ala Val Thr Thr
1 5 10 15
Ser Gln Ile Pro Ala Ser Glu Gln Glu Thr Leu Val Arg Pro Lys Pro
20 25 30
Leu Leu Leu Lys Leu Leu Lys Ser Val Gly Ala Gln Lys Asp Thr Tyr
35 40 45
Thr Met Lys Glu Glu Asn Ile Tyr His Asp Leu Gln Glu Leu Gly Ser
50 55 60
Ser Gln Ser Ala Gly Arg Lys Phe Arg
65 70
<210> 16
<211> 497
<212> PRT
<213> 智人（Homo sapiens）
<400> 16
Met Thr Phe Asn Ser Phe Glu Gly Ser Lys Thr Cys Val Pro Ala Asp
1 5 10 15
Ile Asn Lys Glu Glu Glu Phe Val Glu Glu Phe Asn Arg Leu Lys Thr
20 25 30
Phe Ala Asn Phe Pro Ser Gly Ser Pro Val Ser Ala Ser Thr Leu Ala
35 40 45
Arg Ala Gly Phe Leu Tyr Thr Gly Glu Gly Asp Thr Val Arg Cys Phe
50 55 60
Ser Cys His Ala Ala Val Asp Arg Trp Gln Tyr Gly Asp Ser Ala Val
65 70 75 80
Gly Arg His Arg Lys Val Ser Pro Asn Cys Arg Phe Ile Asn Gly Phe
85 90 95
Tyr Leu Glu Asn Ser Ala Thr Gln Ser Thr Asn Ser Gly Ile Gln Asn
100 105 110
Gly Gln Tyr Lys Val Glu Asn Tyr Leu Gly Ser Arg Asp His Phe Ala
115 120 125
Leu Asp Arg Pro Ser Glu Thr His Ala Asp Tyr Leu Leu Arg Thr Gly
130 135 140
Gln Val Val Asp Ile Ser Asp Thr Ile Tyr Pro Arg Asn Pro Ala Met
145 150 155 160
Tyr Ser Glu Glu Ala Arg Leu Lys Ser Phe Gln Asn Trp Pro Asp Tyr
165 170 175
Ala His Leu Thr Pro Arg Glu Leu Ala Ser Ala Gly Leu Tyr Tyr Thr
180 185 190
Gly Ile Gly Asp Gln Val Gln Cys Phe Cys Cys Gly Gly Lys Leu Lys
195 200 205
Asn Trp Glu Pro Cys Asp Arg Ala Trp Ser Glu His Arg Arg His Phe
210 215 220
Pro Asn Cys Phe Phe Val Leu Gly Arg Asn Leu Asn Ile Arg Ser Glu
225 230 235 240
Ser Asp Ala Val Ser Ser Asp Arg Asn Phe Pro Asn Ser Thr Asn Leu
245 250 255
Pro Arg Asn Pro Ser Met Ala Asp Tyr Glu Ala Arg Ile Phe Thr Phe
260 265 270
Gly Thr Trp Ile Tyr Ser Val Asn Lys Glu Gln Leu Ala Arg Ala Gly
275 280 285
Phe Tyr Ala Leu Gly Glu Gly Asp Lys Val Lys Cys Phe His Cys Gly
290 295 300
Gly Gly Leu Thr Asp Trp Lys Pro Ser Glu Asp Pro Trp Glu Gln His
305 310 315 320
Ala Lys Trp Tyr Pro Gly Cys Lys Tyr Leu Leu Glu Gln Lys Gly Gln
325 330 335
Glu Tyr Ile Asn Asn Ile His Leu Thr His Ser Leu Glu Glu Cys Leu
340 345 350
Val Arg Thr Thr Glu Lys Thr Pro Ser Leu Thr Arg Arg Ile Asp Asp
355 360 365
Thr Ile Phe Gln Asn Pro Met Val Gln Glu Ala Ile Arg Met Gly Phe
370 375 380
Ser Phe Lys Asp Ile Lys Lys Ile Met Glu Glu Lys Ile Gln Ile Ser
385 390 395 400
Gly Ser Asn Tyr Lys Ser Leu Glu Val Leu Val Ala Asp Leu Val Asn
405 410 415
Ala Gln Lys Asp Ser Met Gln Asp Glu Ser Ser Gln Thr Ser Leu Gln
420 425 430
Lys Glu Ile Ser Thr Glu Glu Gln Leu Arg Arg Leu Gln Glu Glu Lys
435 440 445
Leu Cys Lys Ile Cys Met Asp Arg Asn Ile Ala Ile Val Phe Val Pro
450 455 460
Cys Gly His Leu Val Thr Cys Lys Gln Cys Ala Glu Ala Val Asp Lys
465 470 475 480
Cys Pro Met Cys Tyr Thr Val Ile Thr Phe Lys Gln Lys Ile Phe Met
485 490 495
Ser
<210> 17
<211> 618
<212> PRT
<213> 智人（Homo sapiens）
<400> 17
Met His Lys Thr Ala Ser Gln Arg Leu Phe Pro Gly Pro Ser Tyr Gln
1 5 10 15
Asn Ile Lys Ser Ile Met Glu Asp Ser Thr Ile Leu Ser Asp Trp Thr
20 25 30
Asn Ser Asn Lys Gln Lys Met Lys Tyr Asp Phe Ser Cys Glu Leu Tyr
35 40 45
Arg Met Ser Thr Tyr Ser Thr Phe Pro Ala Gly Val Pro Val Ser Glu
50 55 60
Arg Ser Leu Ala Arg Ala Gly Phe Tyr Tyr Thr Gly Val Asn Asp Lys
65 70 75 80
Val Lys Cys Phe Cys Cys Gly Leu Met Leu Asp Asn Trp Lys Leu Gly
85 90 95
Asp Ser Pro Ile Gln Lys His Lys Gln Leu Tyr Pro Ser Cys Ser Phe
100 105 110
Ile Gln Asn Leu Val Ser Ala Ser Leu Gly Ser Thr Ser Lys Asn Thr
115 120 125
Ser Pro Met Arg Asn Ser Phe Ala His Ser Leu Ser Pro Thr Leu Glu
130 135 140
His Ser Ser Leu Phe Ser Gly Ser Tyr Ser Ser Leu Ser Pro Asn Pro
145 150 155 160
Leu Asn Ser Arg Ala Val Glu Asp Ile Ser Ser Ser Arg Thr Asn Pro
165 170 175
Tyr Ser Tyr Ala Met Ser Thr Glu Glu Ala Arg Phe Leu Thr Tyr His
180 185 190
Met Trp Pro Leu Thr Phe Leu Ser Pro Ser Glu Leu Ala Arg Ala Gly
195 200 205
Phe Tyr Tyr Ile Gly Pro Gly Asp Arg Val Ala Cys Phe Ala Cys Gly
210 215 220
Gly Lys Leu Ser Asn Trp Glu Pro Lys Asp Asp Ala Met Ser Glu His
225 230 235 240
Arg Arg His Phe Pro Asn Cys Pro Phe Leu Glu Asn Ser Leu Glu Thr
245 250 255
Leu Arg Phe Ser Ile Ser Asn Leu Ser Met Gln Thr His Ala Ala Arg
260 265 270
Met Arg Thr Phe Met Tyr Trp Pro Ser Ser Val Pro Val Gln Pro Glu
275 280 285
Gln Leu Ala Ser Ala Gly Phe Tyr Tyr Val Gly Arg Asn Asp Asp Val
290 295 300
Lys Cys Phe Cys Cys Asp Gly Gly Leu Arg Cys Trp Glu Ser Gly Asp
305 310 315 320
Asp Pro Trp Val Glu His Ala Lys Trp Phe Pro Arg Cys Glu Phe Leu
325 330 335
Ile Arg Met Lys Gly Gln Glu Phe Val Asp Glu Ile Gln Gly Arg Tyr
340 345 350
Pro His Leu Leu Glu Gln Leu Leu Ser Thr Ser Asp Thr Thr Gly Glu
355 360 365
Glu Asn Ala Asp Pro Pro Ile Ile His Phe Gly Pro Gly Glu Ser Ser
370 375 380
Ser Glu Asp Ala Val Met Met Asn Thr Pro Val Val Lys Ser Ala Leu
385 390 395 400
Glu Met Gly Phe Asn Arg Asp Leu Val Lys Gln Thr Val Gln Ser Lys
405 410 415
Ile Leu Thr Thr Gly Glu Asn Tyr Lys Thr Val Asn Asp Ile Val Ser
420 425 430
Ala Leu Leu Asn Ala Glu Asp Glu Lys Arg Glu Glu Glu Lys Glu Lys
435 440 445
Gln Ala Glu Glu Met Ala Ser Asp Asp Leu Ser Leu Ile Arg Lys Asn
450 455 460
Arg Met Ala Leu Phe Gln Gln Leu Thr Cys Val Leu Pro Ile Leu Asp
465 470 475 480
Asn Leu Leu Lys Ala Asn Val Ile Asn Lys Gln Glu His Asp Ile Ile
485 490 495
Lys Gln Lys Thr Gln Ile Pro Leu Gln Ala Arg Glu Leu Ile Asp Thr
500 505 510
Ile Leu Val Lys Gly Asn Ala Ala Ala Asn Ile Phe Lys Asn Cys Leu
515 520 525
Lys Glu Ile Asp Ser Thr Leu Tyr Lys Asn Leu Phe Val Asp Lys Asn
530 535 540
Met Lys Tyr Ile Pro Thr Glu Asp Val Ser Gly Leu Ser Leu Glu Glu
545 550 555 560
Gln Leu Arg Arg Leu Gln Glu Glu Arg Thr Cys Lys Val Cys Met Asp
565 570 575
Lys Glu Val Ser Val Val Phe Ile Pro Cys Gly His Leu Val Val Cys
580 585 590
Gln Glu Cys Ala Pro Ser Leu Arg Lys Cys Pro Ile Cys Arg Gly Ile
595 600 605
Ile Lys Gly Thr Val Arg Thr Phe Leu Ser
610 615
<210> 18
<211> 298
<212> PRT
<213> 智人（Homo sapiens）
<400> 18
Met Gly Pro Lys Asp Ser Ala Lys Cys Leu His Arg Gly Pro Gln Pro
1 5 10 15
Ser His Trp Ala Ala Gly Asp Gly Pro Thr Gln Glu Arg Cys Gly Pro
20 25 30
Arg Ser Leu Gly Ser Pro Val Leu Gly Leu Asp Thr Cys Arg Ala Trp
35 40 45
Asp His Val Asp Gly Gln Ile Leu Gly Gln Leu Arg Pro Leu Thr Glu
50 55 60
Glu Glu Glu Glu Glu Gly Ala Gly Ala Thr Leu Ser Arg Gly Pro Ala
65 70 75 80
Phe Pro Gly Met Gly Ser Glu Glu Leu Arg Leu Ala Ser Phe Tyr Asp
85 90 95
Trp Pro Leu Thr Ala Glu Val Pro Pro Glu Leu Leu Ala Ala Ala Gly
100 105 110
Phe Phe His Thr Gly His Gln Asp Lys Val Arg Cys Phe Phe Cys Tyr
115 120 125
Gly Gly Leu Gln Ser Trp Lys Arg Gly Asp Asp Pro Trp Thr Glu His
130 135 140
Ala Lys Trp Phe Pro Ser Cys Gln Phe Leu Leu Arg Ser Lys Gly Arg
145 150 155 160
Asp Phe Val His Ser Val Gln Glu Thr His Ser Gln Leu Leu Gly Ser
165 170 175
Trp Asp Pro Trp Glu Glu Pro Glu Asp Ala Ala Pro Val Ala Pro Ser
180 185 190
Val Pro Ala Ser Gly Tyr Pro Glu Leu Pro Thr Pro Arg Arg Glu Val
195 200 205
Gln Ser Glu Ser Ala Gln Glu Pro Gly Gly Val Ser Pro Ala Glu Ala
210 215 220
Gln Arg Ala Trp Trp Val Leu Glu Pro Pro Gly Ala Arg Asp Val Glu
225 230 235 240
Ala Gln Leu Arg Arg Leu Gln Glu Glu Arg Thr Cys Lys Val Cys Leu
245 250 255
Asp Arg Ala Val Ser Ile Val Phe Val Pro Cys Gly His Leu Val Cys
260 265 270
Ala Glu Cys Ala Pro Gly Leu Gln Leu Cys Pro Ile Cys Arg Ala Pro
275 280 285
Val Arg Ser Arg Val Arg Thr Phe Leu Ser
290 295
<210> 19
<211> 213
<212> PRT
<213> 智人（Homo sapiens）
<400> 19
Met Pro Arg Arg Ala Glu Asn Trp Asp Glu Ala Glu Val Gly Ala Glu
1 5 10 15
Glu Ala Gly Val Glu Glu Tyr Gly Pro Glu Glu Asp Gly Gly Glu Glu
20 25 30
Ser Gly Ala Glu Glu Ser Gly Pro Glu Glu Ser Gly Pro Glu Glu Leu
35 40 45
Gly Ala Glu Glu Glu Met Glu Ala Gly Arg Pro Arg Pro Val Leu Arg
50 55 60
Ser Val Asn Ser Arg Glu Pro Ser Gln Val Ile Phe Cys Asn Arg Ser
65 70 75 80
Pro Arg Val Val Leu Pro Val Trp Leu Asn Phe Asp Gly Glu Pro Gln
85 90 95
Pro Tyr Pro Thr Leu Pro Pro Gly Thr Gly Arg Arg Ile His Ser Tyr
100 105 110
Arg Gly His Leu Trp Leu Phe Arg Asp Ala Gly Thr His Asp Gly Leu
115 120 125
Leu Val Asn Gln Thr Glu Leu Phe Val Pro Ser Leu Asn Val Asp Gly
130 135 140
Gln Pro Ile Phe Ala Asn Ile Thr Leu Pro Val Tyr Thr Leu Lys Glu
145 150 155 160
Arg Cys Leu Gln Val Val Arg Ser Leu Val Lys Pro Glu Asn Tyr Arg
165 170 175
Arg Leu Asp Ile Val Arg Ser Leu Tyr Glu Asp Leu Glu Asp His Pro
180 185 190
Asn Val Gln Lys Asp Leu Glu Arg Leu Thr Gln Glu Arg Ile Ala His
195 200 205
Gln Arg Met Gly Asp
210
<210> 20
<211> 172
<212> PRT
<213> 智人（Homo sapiens）
<400> 20
Met Pro Arg Arg Ala Glu Asn Trp Asp Glu Ala Glu Val Gly Ala Glu
1 5 10 15
Glu Ala Gly Val Glu Glu Tyr Gly Pro Glu Glu Asp Gly Gly Glu Glu
20 25 30
Ser Gly Ala Glu Glu Ser Gly Pro Glu Glu Ser Gly Pro Glu Glu Leu
35 40 45
Gly Ala Glu Glu Glu Met Glu Ala Gly Arg Pro Arg Pro Val Leu Arg
50 55 60
Ser Val Asn Ser Arg Glu Pro Ser Gln Val Ile Phe Cys Asn Arg Ser
65 70 75 80
Pro Arg Val Val Leu Pro Val Trp Leu Asn Phe Asp Gly Glu Pro Gln
85 90 95
Pro Tyr Pro Thr Leu Pro Pro Gly Thr Gly Arg Arg Ile His Ser Tyr
100 105 110
Arg Val Tyr Thr Leu Lys Glu Arg Cys Leu Gln Val Val Arg Ser Leu
115 120 125
Val Lys Pro Glu Asn Tyr Arg Arg Leu Asp Ile Val Arg Ser Leu Tyr
130 135 140
Glu Asp Leu Glu Asp His Pro Asn Val Gln Lys Asp Leu Glu Arg Leu
145 150 155 160
Thr Gln Glu Arg Ile Ala His Gln Arg Met Gly Asp
165 170
<210> 21
<211> 193
<212> PRT
<213> 智人（Homo sapiens）
<400> 21
Met Pro Arg Arg Ala Glu Asn Trp Asp Glu Ala Glu Val Gly Ala Glu
1 5 10 15
Glu Ala Gly Val Glu Glu Tyr Gly Pro Glu Glu Asp Gly Gly Glu Glu
20 25 30
Ser Gly Ala Glu Glu Ser Gly Pro Glu Glu Ser Gly Pro Glu Glu Leu
35 40 45
Gly Ala Glu Glu Glu Met Glu Ala Gly Arg Pro Arg Pro Val Leu Arg
50 55 60
Ser Val Asn Ser Arg Glu Pro Ser Gln Val Ile Phe Cys Asn Arg Ser
65 70 75 80
Pro Arg Val Val Leu Pro Val Trp Leu Asn Phe Asp Gly Glu Pro Gln
85 90 95
Pro Tyr Pro Thr Leu Pro Pro Gly Thr Gly Arg Arg Ile His Ser Tyr
100 105 110
Arg Val Leu Met Thr Pro Val Gly Gln Phe Cys Val Val Pro Ala Leu
115 120 125
Val Glu Asn Thr Phe Leu Leu Gly Arg Leu Thr Asp Ala Lys Thr Gly
130 135 140
Thr Ser Gln Gly His Val Gly Ala Gly Arg Ala Asp Arg Val Trp Arg
145 150 155 160
Gly Lys Leu Thr Tyr Leu Pro Ala Gly Arg Trp Arg Gly Cys Gly Cys
165 170 175
Val Val Ser Val Lys Glu His Phe Pro Glu Lys Glu Glu Ser Arg Met
180 185 190
Glu
<210> 22
<211> 442
<212> PRT
<213> 智人（Homo sapiens）
<400> 22
Met Ala Gly Glu Gly Asp Gln Gln Asp Ala Ala His Asn Met Gly Asn
1 5 10 15
His Leu Pro Leu Leu Pro Ala Glu Ser Glu Glu Glu Asp Glu Met Glu
20 25 30
Val Glu Asp Gln Asp Ser Lys Glu Ala Lys Lys Pro Asn Ile Ile Asn
35 40 45
Phe Asp Thr Ser Leu Pro Thr Ser His Thr Tyr Leu Gly Ala Asp Met
50 55 60
Glu Glu Phe His Gly Arg Thr Leu His Asp Asp Asp Ser Cys Gln Val
65 70 75 80
Ile Pro Val Leu Pro Gln Val Met Met Ile Leu Ile Pro Gly Gln Thr
85 90 95
Leu Pro Leu Gln Leu Phe His Pro Gln Glu Val Ser Met Val Arg Asn
100 105 110
Leu Ile Gln Lys Asp Arg Thr Phe Ala Val Leu Ala Tyr Ser Asn Val
115 120 125
Gln Glu Arg Glu Ala Gln Phe Gly Thr Thr Ala Glu Ile Tyr Ala Tyr
130 135 140
Arg Glu Glu Gln Asp Phe Gly Ile Glu Ile Val Lys Val Lys Ala Ile
145 150 155 160
Gly Arg Gln Arg Phe Lys Val Leu Glu Leu Arg Thr Gln Ser Asp Gly
165 170 175
Ile Gln Gln Ala Lys Val Gln Ile Leu Pro Glu Cys Val Leu Pro Ser
180 185 190
Thr Met Ser Ala Val Gln Leu Glu Ser Leu Asn Lys Cys Gln Ile Phe
195 200 205
Pro Ser Lys Pro Val Ser Arg Glu Asp Gln Cys Ser Tyr Lys Trp Trp
210 215 220
Gln Lys Tyr Gln Lys Arg Lys Phe His Cys Ala Asn Leu Thr Ser Trp
225 230 235 240
Pro Arg Trp Leu Tyr Ser Leu Tyr Asp Ala Glu Thr Leu Met Asp Arg
245 250 255
Ile Lys Lys Gln Leu Arg Glu Trp Asp Glu Asn Leu Lys Asp Asp Ser
260 265 270
Leu Pro Ser Asn Pro Ile Asp Phe Ser Tyr Arg Val Ala Ala Cys Leu
275 280 285
Pro Ile Asp Asp Val Leu Arg Ile Gln Leu Leu Lys Ile Gly Ser Ala
290 295 300
Ile Gln Arg Leu Arg Cys Glu Leu Asp Ile Met Asn Lys Cys Thr Ser
305 310 315 320
Leu Cys Cys Lys Gln Cys Gln Glu Thr Glu Ile Thr Thr Lys Asn Glu
325 330 335
Ile Phe Ser Leu Ser Leu Cys Gly Pro Met Ala Ala Tyr Val Asn Pro
340 345 350
His Gly Tyr Val His Glu Thr Leu Thr Val Tyr Lys Ala Cys Asn Leu
355 360 365
Asn Leu Ile Gly Arg Pro Ser Thr Glu His Ser Trp Phe Pro Gly Tyr
370 375 380
Ala Trp Thr Val Ala Gln Cys Lys Ile Cys Ala Ser His Ile Gly Trp
385 390 395 400
Lys Phe Thr Ala Thr Lys Lys Asp Met Ser Pro Gln Lys Phe Trp Gly
405 410 415
Leu Thr Arg Ser Ala Leu Leu Pro Thr Ile Pro Asp Thr Glu Asp Glu
420 425 430
Ile Ser Pro Asp Lys Val Ile Leu Cys Leu
435 440
<210> 23
<211> 441
<212> PRT
<213> 智人（Homo sapiens）
<400> 23
Met Ala Gly Glu Gly Asp Gln Gln Asp Ala Ala His Asn Met Gly Asn
1 5 10 15
His Leu Pro Leu Leu Pro Glu Ser Glu Glu Glu Asp Glu Met Glu Val
20 25 30
Glu Asp Gln Asp Ser Lys Glu Ala Lys Lys Pro Asn Ile Ile Asn Phe
35 40 45
Asp Thr Ser Leu Pro Thr Ser His Thr Tyr Leu Gly Ala Asp Met Glu
50 55 60
Glu Phe His Gly Arg Thr Leu His Asp Asp Asp Ser Cys Gln Val Ile
65 70 75 80
Pro Val Leu Pro Gln Val Met Met Ile Leu Ile Pro Gly Gln Thr Leu
85 90 95
Pro Leu Gln Leu Phe His Pro Gln Glu Val Ser Met Val Arg Asn Leu
100 105 110
Ile Gln Lys Asp Arg Thr Phe Ala Val Leu Ala Tyr Ser Asn Val Gln
115 120 125
Glu Arg Glu Ala Gln Phe Gly Thr Thr Ala Glu Ile Tyr Ala Tyr Arg
130 135 140
Glu Glu Gln Asp Phe Gly Ile Glu Ile Val Lys Val Lys Ala Ile Gly
145 150 155 160
Arg Gln Arg Phe Lys Val Leu Glu Leu Arg Thr Gln Ser Asp Gly Ile
165 170 175
Gln Gln Ala Lys Val Gln Ile Leu Pro Glu Cys Val Leu Pro Ser Thr
180 185 190
Met Ser Ala Val Gln Leu Glu Ser Leu Asn Lys Cys Gln Ile Phe Pro
195 200 205
Ser Lys Pro Val Ser Arg Glu Asp Gln Cys Ser Tyr Lys Trp Trp Gln
210 215 220
Lys Tyr Gln Lys Arg Lys Phe His Cys Ala Asn Leu Thr Ser Trp Pro
225 230 235 240
Arg Trp Leu Tyr Ser Leu Tyr Asp Ala Glu Thr Leu Met Asp Arg Ile
245 250 255
Lys Lys Gln Leu Arg Glu Trp Asp Glu Asn Leu Lys Asp Asp Ser Leu
260 265 270
Pro Ser Asn Pro Ile Asp Phe Ser Tyr Arg Val Ala Ala Cys Leu Pro
275 280 285
Ile Asp Asp Val Leu Arg Ile Gln Leu Leu Lys Ile Gly Ser Ala Ile
290 295 300
Gln Arg Leu Arg Cys Glu Leu Asp Ile Met Asn Lys Cys Thr Ser Leu
305 310 315 320
Cys Cys Lys Gln Cys Gln Glu Thr Glu Ile Thr Thr Lys Asn Glu Ile
325 330 335
Phe Ser Leu Ser Leu Cys Gly Pro Met Ala Ala Tyr Val Asn Pro His
340 345 350
Gly Tyr Val His Glu Thr Leu Thr Val Tyr Lys Ala Cys Asn Leu Asn
355 360 365
Leu Ile Gly Arg Pro Ser Thr Glu His Ser Trp Phe Pro Gly Tyr Ala
370 375 380
Trp Thr Val Ala Gln Cys Lys Ile Cys Ala Ser His Ile Gly Trp Lys
385 390 395 400
Phe Thr Ala Thr Lys Lys Asp Met Ser Pro Gln Lys Phe Trp Gly Leu
405 410 415
Thr Arg Ser Ala Leu Leu Pro Thr Ile Pro Asp Thr Glu Asp Glu Ile
420 425 430
Ser Pro Asp Lys Val Ile Leu Cys Leu
435 440
<210> 24
<211> 379
<212> PRT
<213> 智人（Homo sapiens）
<400> 24
Met Glu Glu Phe His Gly Arg Thr Leu His Asp Asp Asp Ser Cys Gln
1 5 10 15
Val Ile Pro Val Leu Pro Gln Val Met Met Ile Leu Ile Pro Gly Gln
20 25 30
Thr Leu Pro Leu Gln Leu Phe His Pro Gln Glu Val Ser Met Val Arg
35 40 45
Asn Leu Ile Gln Lys Asp Arg Thr Phe Ala Val Leu Ala Tyr Ser Asn
50 55 60
Val Gln Glu Arg Glu Ala Gln Phe Gly Thr Thr Ala Glu Ile Tyr Ala
65 70 75 80
Tyr Arg Glu Glu Gln Asp Phe Gly Ile Glu Ile Val Lys Val Lys Ala
85 90 95
Ile Gly Arg Gln Arg Phe Lys Val Leu Glu Leu Arg Thr Gln Ser Asp
100 105 110
Gly Ile Gln Gln Ala Lys Val Gln Ile Leu Pro Glu Cys Val Leu Pro
115 120 125
Ser Thr Met Ser Ala Val Gln Leu Glu Ser Leu Asn Lys Cys Gln Ile
130 135 140
Phe Pro Ser Lys Pro Val Ser Arg Glu Asp Gln Cys Ser Tyr Lys Trp
145 150 155 160
Trp Gln Lys Tyr Gln Lys Arg Lys Phe His Cys Ala Asn Leu Thr Ser
165 170 175
Trp Pro Arg Trp Leu Tyr Ser Leu Tyr Asp Ala Glu Thr Leu Met Asp
180 185 190
Arg Ile Lys Lys Gln Leu Arg Glu Trp Asp Glu Asn Leu Lys Asp Asp
195 200 205
Ser Leu Pro Ser Asn Pro Ile Asp Phe Ser Tyr Arg Val Ala Ala Cys
210 215 220
Leu Pro Ile Asp Asp Val Leu Arg Ile Gln Leu Leu Lys Ile Gly Ser
225 230 235 240
Ala Ile Gln Arg Leu Arg Cys Glu Leu Asp Ile Met Asn Lys Cys Thr
245 250 255
Ser Leu Cys Cys Lys Gln Cys Gln Glu Thr Glu Ile Thr Thr Lys Asn
260 265 270
Glu Ile Phe Ser Leu Ser Leu Cys Gly Pro Met Ala Ala Tyr Val Asn
275 280 285
Pro His Gly Tyr Val His Glu Thr Leu Thr Val Tyr Lys Ala Cys Asn
290 295 300
Leu Asn Leu Ile Gly Arg Pro Ser Thr Glu His Ser Trp Phe Pro Gly
305 310 315 320
Tyr Ala Trp Thr Val Ala Gln Cys Lys Ile Cys Ala Ser His Ile Gly
325 330 335
Trp Lys Phe Thr Ala Thr Lys Lys Asp Met Ser Pro Gln Lys Phe Trp
340 345 350
Gly Leu Thr Arg Ser Ala Leu Leu Pro Thr Ile Pro Asp Thr Glu Asp
355 360 365
Glu Ile Ser Pro Asp Lys Val Ile Leu Cys Leu
370 375
<210> 25
<211> 398
<212> PRT
<213> 智人（Homo sapiens）
<400> 25
Met Ala Gly Glu Gly Asp Gln Gln Asp Ala Ala His Asn Met Gly Asn
1 5 10 15
His Leu Pro Leu Leu Pro Ala Glu Ser Glu Glu Glu Asp Glu Met Glu
20 25 30
Val Glu Asp Gln Asp Ser Lys Glu Ala Lys Lys Pro Asn Ile Ile Asn
35 40 45
Phe Asp Thr Ser Leu Pro Thr Ser His Thr Tyr Leu Gly Ala Asp Met
50 55 60
Glu Glu Phe His Gly Arg Thr Leu His Asp Asp Asp Ser Cys Gln Val
65 70 75 80
Ile Pro Val Leu Pro Gln Val Met Met Ile Leu Ile Pro Gly Gln Thr
85 90 95
Leu Pro Leu Gln Leu Phe His Pro Gln Glu Val Ser Met Val Arg Asn
100 105 110
Leu Ile Gln Lys Asp Arg Thr Phe Ala Val Leu Ala Tyr Ser Asn Val
115 120 125
Gln Glu Arg Glu Ala Gln Phe Gly Thr Thr Ala Glu Ile Tyr Ala Tyr
130 135 140
Arg Glu Glu Gln Asp Phe Gly Ile Glu Ile Val Lys Val Lys Ala Ile
145 150 155 160
Gly Arg Gln Arg Phe Lys Val Leu Glu Leu Arg Thr Gln Ser Asp Gly
165 170 175
Ile Gln Gln Ala Lys Val Gln Ile Leu Pro Glu Cys Val Leu Pro Ser
180 185 190
Thr Met Ser Ala Val Gln Leu Glu Ser Leu Asn Lys Cys Gln Ile Phe
195 200 205
Pro Ser Lys Pro Val Ser Arg Glu Asp Gln Cys Ser Tyr Lys Trp Trp
210 215 220
Gln Lys Tyr Gln Lys Arg Lys Phe His Cys Ala Asn Leu Thr Ser Trp
225 230 235 240
Pro Arg Trp Leu Tyr Ser Leu Tyr Asp Ala Glu Thr Leu Met Asp Arg
245 250 255
Ile Lys Lys Gln Leu Arg Glu Trp Asp Glu Asn Leu Lys Asp Asp Ser
260 265 270
Leu Pro Ser Asn Pro Ile Asp Phe Ser Tyr Arg Val Ala Ala Cys Leu
275 280 285
Pro Ile Asp Asp Val Leu Arg Ile Gln Leu Leu Lys Ile Gly Ser Ala
290 295 300
Ile Gln Arg Leu Arg Cys Glu Leu Asp Ile Met Asn Lys Cys Thr Ser
305 310 315 320
Leu Cys Cys Lys Gln Cys Gln Glu Thr Glu Ile Thr Thr Lys Asn Glu
325 330 335
Ile Phe Arg Tyr Ala Trp Thr Val Ala Gln Cys Lys Ile Cys Ala Ser
340 345 350
His Ile Gly Trp Lys Phe Thr Ala Thr Lys Lys Asp Met Ser Pro Gln
355 360 365
Lys Phe Trp Gly Leu Thr Arg Ser Ala Leu Leu Pro Thr Ile Pro Asp
370 375 380
Thr Glu Asp Glu Ile Ser Pro Asp Lys Val Ile Leu Cys Leu
385 390 395
<210> 26
<211> 475
<212> PRT
<213> 智人（Homo sapiens）
<400> 26
Met Ala Ser Ala Ala Arg Leu Thr Met Met Trp Glu Glu Val Thr Cys
1 5 10 15
Pro Ile Cys Leu Asp Pro Phe Val Glu Pro Val Ser Ile Glu Cys Gly
20 25 30
His Ser Phe Cys Gln Glu Cys Ile Ser Gln Val Gly Lys Gly Gly Gly
35 40 45
Ser Val Cys Pro Val Cys Arg Gln Arg Phe Leu Leu Lys Asn Leu Arg
50 55 60
Pro Asn Arg Gln Leu Ala Asn Met Val Asn Asn Leu Lys Glu Ile Ser
65 70 75 80
Gln Glu Ala Arg Glu Gly Thr Gln Gly Glu Arg Cys Ala Val His Gly
85 90 95
Glu Arg Leu His Leu Phe Cys Glu Lys Asp Gly Lys Ala Leu Cys Trp
100 105 110
Val Cys Ala Gln Ser Arg Lys His Arg Asp His Ala Met Val Pro Leu
115 120 125
Glu Glu Ala Ala Gln Glu Tyr Gln Glu Lys Leu Gln Val Ala Leu Gly
130 135 140
Glu Leu Arg Arg Lys Gln Glu Leu Ala Glu Lys Leu Glu Val Glu Ile
145 150 155 160
Ala Ile Lys Arg Ala Asp Trp Lys Lys Thr Val Glu Thr Gln Lys Ser
165 170 175
Arg Ile His Ala Glu Phe Val Gln Gln Lys Asn Phe Leu Val Glu Glu
180 185 190
Glu Gln Arg Gln Leu Gln Glu Leu Glu Lys Asp Glu Arg Glu Gln Leu
195 200 205
Arg Ile Leu Gly Glu Lys Glu Ala Lys Leu Ala Gln Gln Ser Gln Ala
210 215 220
Leu Gln Glu Leu Ile Ser Glu Leu Asp Arg Arg Cys His Ser Ser Ala
225 230 235 240
Leu Glu Leu Leu Gln Glu Val Ile Ile Val Leu Glu Arg Ser Glu Ser
245 250 255
Trp Asn Leu Lys Asp Leu Asp Ile Thr Ser Pro Glu Leu Arg Ser Val
260 265 270
Cys His Val Pro Gly Leu Lys Lys Met Leu Arg Thr Cys Ala Val His
275 280 285
Ile Thr Leu Asp Pro Asp Thr Ala Asn Pro Trp Leu Ile Leu Ser Glu
290 295 300
Asp Arg Arg Gln Val Arg Leu Gly Asp Thr Gln Gln Ser Ile Pro Gly
305 310 315 320
Asn Glu Glu Arg Phe Asp Ser Tyr Pro Met Val Leu Gly Ala Gln His
325 330 335
Phe His Ser Gly Lys His Tyr Trp Glu Val Asp Val Thr Gly Lys Glu
340 345 350
Ala Trp Asp Leu Gly Val Cys Arg Asp Ser Val Arg Arg Lys Gly His
355 360 365
Phe Leu Leu Ser Ser Lys Ser Gly Phe Trp Thr Ile Trp Leu Trp Asn
370 375 380
Lys Gln Lys Tyr Glu Ala Gly Thr Tyr Pro Gln Thr Pro Leu His Leu
385 390 395 400
Gln Val Pro Pro Cys Gln Val Gly Ile Phe Leu Asp Tyr Glu Ala Gly
405 410 415
Met Val Ser Phe Tyr Asn Ile Thr Asp His Gly Ser Leu Ile Tyr Ser
420 425 430
Phe Ser Glu Cys Ala Phe Thr Gly Pro Leu Arg Pro Phe Phe Ser Pro
435 440 445
Gly Phe Asn Asp Gly Gly Lys Asn Thr Ala Pro Leu Thr Leu Cys Pro
450 455 460
Leu Asn Ile Gly Ser Gln Gly Ser Thr Asp Tyr
465 470 475
<210> 27
<211> 22
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 27
tgtttgaatg aggcttcagt ac 22
<210> 28
<211> 43
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 28
aggcgcgaag actcaattga aggctcgaga aggtatattg ctg 43
<210> 29
<211> 40
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 29
cacttttttc aattgacacg tacgcgtatt ctaccgggta 40
<210> 30
<211> 20
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 30
agagtggatg ggcaagaagc 20
<210> 31
<211> 22
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 31
aagatggagt cattgctgtt ca 22
<210> 32
<211> 21
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 32
gattgactct ccctcaccac t 21
<210> 33
<211> 22
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 33
ctgtgtacaa gagcagaggt tc 22
<210> 34
<211> 20
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 34
tgcttgagct caggacagtg 20
<210> 35
<211> 20
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 35
actaagacca agatggggcc 20
<210> 36
<211> 20
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 36
gctggtgtgg gcagattgct 20
<210> 37
<211> 21
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 37
cactgctaca gcctcacact g 21
<210> 38
<211> 20
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 38
gattgcctgc attcgctctg 20
<210> 39
<211> 20
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 39
atgctgctgt ttggatgggt 20
<210> 40
<211> 21
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 40
gttctcatgg catctccaag g 21
<210> 41
<211> 22
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 41
gactgttgtg agcatgaagt tc 22
<210> 42
<211> 21
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 42
gagggcctat ttcccatgat t 21
<210> 43
<211> 43
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 43
ccagctgaag ctcatgaact acagtctgct ggtgggaatt cat 43
<210> 44
<211> 43
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 44
atgaattccc accagcagac tgtagttcat gagcttcagc tgg 43
<210> 45
<211> 47
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 45
taggaaggag gtgtacttca tggcaattat taacatcctt actcatt 47
<210> 46
<211> 47
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 46
aatgagtaag gatgttaata attgccatga agtacacctc cttccta 47
<210> 47
<211> 43
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 47
acagctgaag atcatgaact acagcctgct ggtgggcatc cac 43
<210> 48
<211> 43
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 48
gtggatgccc accagcaggc tgtagttcat gatcttcagc tgt 43
<210> 49
<211> 41
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 49
gtatttcatg gccatcatta atatcctcac gccatacgat a 41
<210> 50
<211> 41
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 50
tatcgtatgg cgtgaggata ttaatgatgg ccatgaaata c 41
<210> 51
<211> 44
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 51
agtgcagctg aagatcatga actacagcct tctgctaggc atcc 44
<210> 52
<211> 44
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 52
ggatgcctag cagaaggctg tagttcatga tcttcagctg cact 44
<210> 53
<211> 46
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 53
ccagaaggag gtctacttca tgggcctcat tgatatcctt acacag 46
<210> 54
<211> 46
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 54
ctgtgtaagg atatcaatga ggcccatgaa gtagacctcc ttctgg 46
<210> 55
<211> 86
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 55
gcatgtaccg gcttaatgtt gatggtgtag agatttacgt cattgtaact aggaacgtat 60
tcagccaccg tttgtctgtg tatagg 86
<210> 56
<211> 86
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 56
cctatacaca gacaaacggt ggctgaatac gttcctagtt acaatgacgt aaatctctac 60
accatcaaca ttaagccggt acatgc 86
<210> 57
<211> 58
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 57
cttccgtaac ctgcgggaaa gattcggtat agacgaccaa gatttccaga attccctg 58
<210> 58
<211> 58
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 58
cagggaattc tggaaatctt ggtcgtctat accgaatctt tcccgcaggt tacggaag 58
<210> 59
<211> 57
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 59
cattgatatc ctcacccctt atgacactaa aaaaaaagct gcacatgctg ccaaaac 57
<210> 60
<211> 57
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 60
gttttggcag catgtgcagc ttttttttta gtgtcataag gggtgaggat atcaatg 57
<210> 61
<211> 57
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 61
ccagcgagga cgtggcggag atgcataata tattgaaaaa gtaccaccag tttatag 57
<210> 62
<211> 57
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 62
ctataaactg gtggtacttt ttcaatatat tatgcatctc cgccacgtcc tcgctgg 57
<210> 63
<211> 36
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 63
ggttatgctg ctgccgaaca atttcaaggc gagcag 36
<210> 64
<211> 36
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 64
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<220>
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attcagggcg agtacatgat cc 22
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<220>
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cacgagaaat gcaacacgtt ac 22
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<210> 77
<211> 26
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 77
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<213> 人工序列（Artificial Sequence）
<220>
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<400> 78
caccttctac aatgagctgc gtgtg 25
<210> 79
<211> 22
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
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tagataagca ttataattcc ta 22
<210> 80
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<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 80
tatcacatat atttcaactc ca 22
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<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
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tacatttctt gtaactatca ca 22
<210> 82
<211> 22
<212> DNA
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<220>
<223> 合成寡核苷酸
<400> 82
tttcttcttt gtatcgtatg gc 22
<210> 83
<211> 22
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 83
tatttcttta agatgttgtg ca 22
<210> 84
<211> 22
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
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<400> 84
ttgaacatca gagagaacca gg 22
<210> 85
<211> 22
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<220>
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<400> 85
ttctaaagag caatggttgc tg 22
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<220>
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<400> 86
tattattata gtaacaggag ca 22
<210> 87
<211> 22
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<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 87
ttgatcatca attccaaacc tc 22
<210> 88
<211> 23
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 88
tcatctggca tcaacataac agg 23
<210> 89
<211> 23
<212> DNA
<213> 人工序列（Artificial Sequence）
<220>
<223> 合成寡核苷酸
<400> 89
gaataggctt tgaagtcatc tgg 23
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<212> DNA
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Val Met Leu Leu Pro Asp Asp
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Phe His Arg Glu Asn Leu Pro
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<213> 智人（Homo sapiens）
<400> 95
Glu Ile Phe Leu Pro Asn Asn
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<210> 96
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Claims (29)
1.一种方法，包括在哺乳动物受试者中或在哺乳动物细胞群中降解、修饰或抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体，使受试者具有经修饰的哺乳动物细胞群或产生经修饰的哺乳动物细胞群。
2.根据权利要求1所述的一种方法，其中，所述一种或多种磷脂酰肌醇-5-磷酸4-激酶是PIP4K2A、PIP4K2B或PIP4K2C。
3.根据权利要求1所述的一种方法，其中，所述磷脂酰肌醇-5-磷酸4-激酶(PIP4K)是PIP4K2B，并且所述受试者患有或疑似患有糖尿病、代谢综合征、胰岛素抵抗、肥胖症或其组合。
4.根据权利要求1所述的一种方法，其中，所述磷脂酰肌醇-5-磷酸4-激酶(PIP4K)是PIP4K2C，并且所述受试者患有或疑似患有癌症、免疫缺陷、自身免疫性疾病、感染或其组合。
5.根据权利要求1所述的一种方法，其在哺乳动物受试者中或在哺乳动物细胞群中能够抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体与一种或多种内源性PIP4K或磷脂酰肌醇-4-磷酸5-激酶发生相互作用，使受试者具有经修饰的哺乳动物细胞群或产生经修饰的哺乳动物细胞群。
6.根据权利要求1所述的一种方法，其能够减少一种或多种所述异构体与至少一种其它磷脂酰肌醇-5-磷酸4-激酶(PIP4K)或磷脂酰肌醇-4-磷酸5-激酶(PIP5K)发生支架作用或相互作用。
7.根据权利要求1所述的一种方法，其能够调节PIP5K活性、PI3K活性或其组合。
8.根据权利要求1所述的一种方法，包括向哺乳动物受试者施用磷脂酰肌醇-5-磷酸4-激酶(包含序列SEQ ID NO:1-5或96中的突变)，其中，X为任何氨基酸。
9.根据权利要求8所述的一种方法，其中，肽具有完整的磷脂酰肌醇-5-磷酸4-激酶(PIP4K)催化位点。
10.根据权利要求1所述的一种方法，其中，在哺乳动物受试者中或在哺乳动物细胞群中降解、修饰或抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体不会阻断或抑制磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体催化位点。
11.根据权利要求1所述的一种方法，其中，降解、修饰或抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括使一个结合部分接触所述一种或多种PIP4K异构体或向所述一种或多种PIP4K异构体施用一个结合部分。
12.根据权利要求11所述的一种方法，其中，所述结合实体与一种或多种PIP4K2A、PIP4K2B或PIP4K2C蛋白特异性结合。
13.根据权利要求11所述的一种方法，其中，所述结合部分与药剂直接或间接连接，药剂向细胞发出信号降解与药剂结合的磷脂酰肌醇-5-磷酸4-激酶。
14.根据权利要求11所述的一种方法，其中，所述结合实体与一个表位特异性结合，所述表位的序列与SEQ ID NO:6、8或10的5个氨基酸到30个氨基酸部分具有至少95％的序列一致性。
15.根据权利要求11所述的一种方法，其中，所述结合实体与一个表位特异性结合，所述表位的序列与SEQ ID NO:1、2、3、4、5、93或96具有至少95％的序列一致性。
16.根据权利要求1所述的一种方法，其中，降解、修饰或抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括抑制至少一种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体与内源性细胞结构或蛋白之间发生结构性相互作用。
17.根据权利要求1所述的一种方法，其中，抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括：(a)施用一种或多种磷脂酰肌醇-5-磷酸4-激酶异构体的抑制剂；或(b)修饰一个或多个磷脂酰肌醇-5-磷酸4-激酶基因序列。
18.根据权利要求1所述的一种方法，其中，抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体的表达或功能。
19.根据权利要求18所述的一种方法，其中，抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体的表达或功能包括施用一种或多种磷脂酰肌醇-5-磷酸4-激酶异构体的抗体、核酸抑制剂或小分子抑制剂。
20.根据权利要求19所述的一种方法，其中，所述抑制剂是一种小发夹RNA、siRNA或能够表达小发夹RNA或siRNA的载体。
21.根据权利要求19所述的一种方法，其中，所述抑制剂是一种与RNA结合的核酸，所述RNA与SEQ ID NO:7、8或11具有至少95％的序列一致性或互补性。
22.根据权利要求19所述的一种方法，其中，所述抑制剂是一种与一种或多种PIP4K2A、PIP4K2B或PIP4K2C蛋白的非催化位点特异性结合的结合实体。
23.根据权利要求1所述的一种方法，其中，修饰一个或多个磷脂酰肌醇-5-磷酸4-激酶基因序列包括CRISPR介导、TALENS介导或ZFN介导的敲除或敲减PIP4K2A、PIP4K2B和/或PIP4K2C。
24.根据权利要求23所述的一种方法，包括从受试者中分离细胞群以及将细胞与一种或多种CRISPR、TALENS或ZFN试剂一起培养产生经修饰的细胞群(包含一个或多个经修饰的磷脂酰肌醇-5-磷酸4-激酶基因序列)。
25.根据权利要求24所述的一种方法，其中，所述一种或多种CRISPR、TALENS或ZFN试剂包含一个或多个向导RNA或一种能够表达一个或多个向导RNA的载体，其中所述一个或多个向导RNA可与PIP4K2A、PIP4K2B或PIP4K2C基因组位点特异性结合。
26.根据权利要求1所述的一种方法，其中，降解、修饰或抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体包括抑制一种或多种磷脂酰肌醇-5-磷酸4-激酶(PIP4K)异构体，使包括SEQ ID NO:1-5或96的PIP4K肽接触受试者或向受试者施用包括SEQ ID NO:1-5或96的PIP4K肽，其中，所述肽不是全长PIP4K。
27.一种试剂盒，包括一个或多个与至少一种磷脂酰肌醇-5-磷酸4-激酶特异性结合的结合部分以及用于施用所述一个或多个结合部分的说明书，其中，所述结合部分与药剂直接或间接连接，药剂向细胞发出信号降解与药剂结合的磷脂酰肌醇-5-磷酸4-激酶。
28.一种包含序列VMLXPDD(SEQ ID NO:96，其中X为任何氨基酸)中突变的磷脂酰肌醇-5-磷酸4-激酶用于治疗糖尿病、代谢综合征、胰岛素抵抗、肥胖症、癌症或其组合的用途。
29.一种或多种磷脂酰肌醇-5-磷酸4-激酶异构体的抗体、核酸抑制剂或小分子抑制剂用于治疗糖尿病、代谢综合征、胰岛素抵抗、肥胖症、癌症或其组合的用途。
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| AU2020270981A1 (en) | 2021-11-04 |
| CA3136354A1 (en) | 2020-10-15 |
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