CN115372626A - Thada在制备糖代谢紊乱疾病筛选试剂中的应用 - Google Patents

Thada在制备糖代谢紊乱疾病筛选试剂中的应用 Download PDF

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CN115372626A
CN115372626A CN202210813396.6A CN202210813396A CN115372626A CN 115372626 A CN115372626 A CN 115372626A CN 202210813396 A CN202210813396 A CN 202210813396A CN 115372626 A CN115372626 A CN 115372626A
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赵涵
张玉青
陈子江
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Abstract

本发明提供了一种THADA在制备糖代谢紊乱疾病筛选试剂中的应用，所述应用为将THADA作为靶点或生物标志物，制备糖代谢紊乱疾病的筛选制剂，应用于预测、筛选或诊断糖代谢紊乱性疾病。本发明提供了THADA高表达可介导2型糖尿病β细胞功能障碍和高血糖的证据，表明THADA可用于预测糖代谢紊乱的发生风险和严重程度，为临床上糖代谢紊乱疾病的预防和筛选提供了理论支持和全新途径。

Description

THADA在制备糖代谢紊乱疾病筛选试剂中的应用
技术领域
本发明属于生物医药领域，涉及一种疾病筛选试剂的制备，特别涉及THADA在制备2型糖尿病、多囊卵巢综合征等糖代谢紊乱性疾病筛选试剂中的应用。
背景技术
随着现代社会不良饮食习惯和生活方式的增长，世界范围内2型糖尿病、肥胖、多囊卵巢综合征、代谢综合征等一系列代谢性疾病的发病率日益升高，成为全球重大公共卫生健康问题。根据2020年发表于英国医学杂志的流行病学调查显示1，中国汉族成人的糖尿病患病率高达12.8%，而使用降糖药物的患者中血糖控制率仅为49.4%。因此，2型糖尿病及相关糖代谢紊乱性疾病的防控形势十分严峻。
胰岛β细胞在机体血糖稳态调控中居于核心地位。胰岛β细胞功能障碍和β细胞容量不足被认为是2型糖尿病发生发展的中心环节2。在2型糖尿病发生发展的自然病程中，长期营养过剩引起机体胰岛素抵抗，胰岛β细胞早期表现为代偿性分泌功能增强及容量增加。随着血糖水平的逐渐升高，β细胞长期高负荷工作以及高糖高脂引发的糖脂毒性和内质网应激等代谢压力，引起β细胞胰岛素分泌功能逐渐衰竭。上述病理变化最终导致机体胰岛素水平的绝对缺乏不足以维持血糖稳态，引起持续高血糖的发生3。
遗传因素在2型糖尿病发病中起重要作用。既往全基因组关联研究（GWAS）发现了多个血糖水平相关的遗传易感基因。其中，甲状腺腺瘤相关基因（THADA）多态性在多个人群GWAS研究中都被发现与2型糖尿病显著相关4。THADA基因最早因参与良性甲状腺腺瘤的染色体重排而被命名。研究显示THADA基因的遗传变异在2型糖尿病母亲到子代中存在过度传递，提示其参与该疾病的发生5。另一研究检测到THADA基因的单核苷酸多态性与2型糖尿病患者的胰岛β细胞反应降低显著相关，而与胰岛素敏感性无关联。在一项中国人群的研究中，THADA基因与口服葡萄糖耐量试验中的2小时胰岛素水平显著相关。上述发现都提示THADA是2型糖尿病的关键候选基因。
除此以外，THADA也是多囊卵巢综合征（PCOS）GWAS研究发现的关键易感基因6，且在不同种族人群中均得以验证。PCOS患者除内分泌紊乱影响生育外，常合并2型糖尿病、肥胖、胰岛素抵抗及代谢综合征等代谢异常。值得注意的是，多囊卵巢综合征患者的THADA风险稳点与空腹血糖水平和代谢综合征的发生率显著相关7，提示THADA同样参与PCOS的发病，该基因很可能是2型糖尿病与PCOS的共同致病基因。
目前对于THADA基因的功能研究十分有限，对其生物学作用所知甚少。Moraru等人发现，在果蝇中敲除THADA基因可导致进食过多、产热减少和脂质储存增加而引起肥胖8。另一项研究显示，拟南芥中THADA同源物的缺失可导致对寒冷的不耐受9。然而，目前THADA在哺乳动物代谢调控中的作用并无研究报道，尤其在糖代谢方面尚无涉及。更为重要的是，未见任何THADA组织表达水平与能量代谢的相关报道，未能对其临床意义开展相关研究。
[1] Li, Y. et al. Prevalence of diabetes recorded in mainland Chinausing 2018 diagnostic criteria from the American Diabetes Association:national cross sectional study. BMJ (Clinical research ed.) 369, m997, doi:10.1136/bmj.m997 (2020).
[2] Ashcroft, F. M. & Rorsman, P. Diabetes mellitus and the betacell: the last ten years. Cell 148,1160-1171, doi:10.1016/j.cell.2012.02.010(2012).
[3] Prentki, M. & Nolan, C. Islet beta cell failure in type 2diabetes. The Journal of clinical investigation 116, 1802-1812, doi:10.1172/jci29103 (2006).
[4] Zeggini, E. et al. Meta-analysis of genome-wide association dataand large-scale replication identifies additional susceptibility loci fortype 2 diabetes. Nature genetics 40, 638-645, doi:10.1038/ng.120 (2008).
[5] Prasad, R. et al. Excess maternal transmission of variants in theTHADA gene to offspring with type 2 diabetes. Diabetologia 59, 1702-1713,doi:10.1007/s00125-016-3973-9 (2016).
[6] Chen, Z. et al. Genome-wide association study identifiessusceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21and 9q33.3. Nature genetics 43, 55-59, doi:10.1038/ng.732 (2011).
[7] Tian, Y. et al. THADA, INSR, TOX3PCOS-GWAS SusceptibilityVariants in , and Are Associated With Metabolic Syndrome or InsulinResistance in Women With PCOS. Frontiers in endocrinology 11, 274, doi:10.3389/fendo.2020.00274 (2020).
[8] Moraru, A. et al. THADA Regulates the Organismal Balance betweenEnergy Storage and Heat Production. Developmental cell 41, 72-81.e76, doi:10.1016/j.devcel.2017.03.016 (2017).
[9] Dong, Y., Teleman, A., Jedmowski, C., Wirtz, M. & Hell, R. TheArabidopsis THADA homologue modulates TOR activity and cold acclimation.Plant biology (Stuttgart, Germany), 77-83, doi:10.1111/plb.12893 (2019)。
发明内容
为临床上评估2型糖尿病、肥胖、多囊卵巢综合征等疾病糖代谢紊乱的发病风险，本发明提供一种THADA在制备糖代谢紊乱疾病筛选试剂中的应用，尤其是THADA在制备2型糖尿病筛选试剂中的应用，以及THADA在制备多囊卵巢综合征糖代谢紊乱筛选试剂中的应用。
为实现上述目的，本发明采用如下技术方案。
一种THADA在制备糖代谢紊乱疾病筛选试剂中的应用。
所述疾病包括但不限于2型糖尿病、多囊卵巢综合征、肥胖及代谢综合征。
所述应用为将THADA作为靶点或生物标志物，制备糖代谢紊乱疾病的筛选制剂，应用于预测、筛选或诊断糖代谢紊乱性疾病，为临床上评估糖代谢紊乱的发病风险提供理论依据。
所述应用包括但不限于：以THADA作为靶点，检测THADA基因的信使RNA表达水平、转录或转录后修饰水平，或THADA蛋白表达水平、翻译后修饰水平，或THADA基因突变、单核苷酸多态性，或THADA蛋白的功能、定位、活性，从而制备糖代谢紊乱性疾病的筛选试剂。
本发明具有以下优点：
本发明首先从正常人和2型糖尿病患者的胰腺切片中发现，胰岛β细胞内THADA表达水平在2型糖尿病患者中显著升高。进一步在2型糖尿病小鼠中发现，胰岛THADA的蛋白水平随疾病进展而逐渐升高，且与血糖水平呈显著正相关。在饮食诱导的2型糖尿病和多囊卵巢综合征小鼠中，THADA表达水平也显著升高。体外研究显示，THADA转录激活可明显抑制β细胞的胰岛素分泌功能。本发明提供了THADA高表达可介导2型糖尿病β细胞功能障碍和高血糖的证据，表明THADA可用于预测糖代谢紊乱的发生风险和严重程度，为临床上糖代谢紊乱疾病的预防和筛选提供了理论支持和全新途径。
附图说明
图1为正常对照和2型糖尿病患者胰岛中的THADA表达水平；
图2为不同周龄的db/db小鼠胰岛中的THADA表达水平及与血糖水平的相关性；
图3为高脂高糖饮食诱导的2型糖尿病、多囊卵巢综合征小鼠胰岛中的THADA表达水平；
图4为dCas9转录激活技术诱导β细胞THADA表达水平升高；
图5为THADA转录激活后抑制小鼠β细胞和原代胰岛的胰岛素分泌功能。
具体实施方式
下面结合实施例和附图对本发明做进一步说明，但本发明不受下述实施例的限制。
实施例1 2型糖尿病患者胰岛的THADA表达水平
本研究纳入因胰腺良性肿瘤行部分胰腺切除术的2型糖尿病患者及正常对照各4例。2型糖尿病的诊断标准为美国糖尿病协会（ADA）标准，并排除诊断为恶性肿瘤者。收集患者术前一周的临床信息，包括性别、年龄、身高、体重、2型糖尿病病程及既往治疗用药；采用空腹静脉血浆标本检测患者的空腹血糖水平；术中取胰腺组织进行福尔马林固定，并进行脱水及石蜡包埋。
表1 正常对照和2型糖尿病患者的临床资料
Figure 534084DEST_PATH_IMAGE001
如表1结果显示，与正常对照相比，2型糖尿病组患者的空腹血糖水平显著升高。对上述病例的胰腺组织取远离肿瘤的胰腺蜡块进行切片，并行免疫荧光染色，于共聚焦荧光显微镜下拍照。绿色荧光指示胰岛素染色，红色荧光指示THADA染色，蓝色荧光指示细胞核DAPI染色。结果如图1所示，与正常对照组相比，2型糖尿病患者中存在强烈的THADA与胰岛素共染色（图1a），提示2型糖尿病患者胰岛β细胞中THADA高表达。进一步对各个染色切片利用Image J图像分析工具进行荧光水平定量结果显示，与对照病例相比，2型糖尿病患者胰岛中THADA的蛋白表达水平显著升高（图1b和1c）。
实施例2 THADA表达水平与血糖水平的相关性
我们进一步利用瘦素受体缺陷的db/db小鼠来研究THADA与糖代谢紊乱的相关性。db/db小鼠随年龄增长出现自发性高血糖、肥胖、高血脂、代谢综合征及雌性不育的表型，是常用的2型糖尿病小鼠研究模型。我们分别取4周龄、8周龄及16周龄的db/db小鼠及同窝野生型对照小鼠。检测小鼠血糖水平可见，db/db小鼠随着年龄增长而血糖水平逐渐升高，上述不同周龄的小鼠即分别处于2型糖尿病前期、2型糖尿病早期及2型糖尿病进展期（图2a）。取上述小鼠胰腺进行固定、脱水和石蜡包埋切片，免疫荧光染色，绿色荧光指示胰岛素染色，红色荧光指示THADA染色，蓝色荧光指示细胞核DAPI染色。结果显示，与血糖正常的对照小鼠相比，db/db小鼠随年龄增长和血糖水平升高，胰岛β细胞中THADA的表达水平逐渐升高（图2b和2c）。进一步对每只小鼠的胰岛中THADA的蛋白表达水平进行定量，并与该小鼠的血糖水平进行相关性分析显示，THADA表达水平与血糖呈显著正相关（图2d）。
实施例3 高脂高糖饮食诱导的小鼠胰岛中THADA表达
为证实THADA与糖代谢紊乱性疾病的相关性，我们采用了另一种饮食诱导的糖代谢损伤小鼠模型。对8周龄的C57BL/6小鼠进行高脂高糖饲料喂养（45%脂肪，35%碳水化合物，其中17%为蔗糖，购自Research Diets公司），持续喂养12周至小鼠20周龄。该饮食模式可诱导小鼠肥胖、血糖升高及糖耐量损伤、胰岛素抵抗、动情周期紊乱及卵巢内分泌功能异常等症状，可用作2型糖尿病及多囊卵巢综合征小鼠模型。
取上述正常饮食及长期高脂高糖饮食喂养的小鼠胰腺，进行石蜡包埋切片及免疫荧光染色，绿色荧光指示胰岛素染色，红色荧光指示THADA染色，蓝色荧光指示细胞核DAPI染色。结果显示，高脂高糖小鼠的胰岛素β细胞中THADA的表达水平比对照小鼠显著升高（图3），证实THADA与糖代谢紊乱的相关性。
实施例4 THADA转录激活后损伤β细胞的胰岛素分泌功能
为了证实THADA高表达介导糖代谢紊乱的作用及机制，我们利用CRISPR-dCas9转录激活技术激活THADA表达，并检测其生物学作用。CRISPR/dCas9-协同激活介质（SAM）系统是一种可选择性地激活内源性基因转录的强大系统。我们利用该系统来激活MIN6细胞（一种常用的小鼠β细胞系）中内源性Thada基因转录，具体实验过程如下：
将MIN6细胞铺入六孔板，24小时贴壁后按MOI=10转染dCAS9慢病毒，12小时后移去病毒培液并换成正常培养基。72小时后，于转染细胞加入10 μg/mL的嘌呤霉素筛选，存活细胞即为dCas9转染成功细胞。将该稳转株继续以2 μg/mL的嘌呤霉素培养，待细胞状态稳定后继续转染含sgRNA-MS2-P65-HSF1转录共激活因子的慢病毒。转染72小时后予以1 mg/mL的遗传霉素筛选，存活细胞即为转染成功细胞。sgRNA特异性靶向小鼠Thada基因的启动子区，序列如下：5’-ATCAAGAACTGTTTAGTCGC-3’。
验证上述转录激活后THADA的表达水平显示，THADA基因的mRNA和蛋白表达水平均显著升高（比对照细胞平均升高约2.5倍）（图4a和4b）。进一步检测胰岛素分泌功能实验显示，THADA转录激活后，不同浓度葡萄糖刺激的胰岛素分泌水平均显著降低（图5a）。同时，KCl去极化刺激和甲苯磺丁脲刺激的胰岛素分泌量也显著降低（图5b）。在小鼠原代胰岛中，利用dCas9系统激活THADA转录后，也同样观察到葡萄糖刺激的胰岛素分泌显著减少（图5c）。上述结果证实，THADA高表达通过损伤胰岛β细胞的胰岛素分泌功能，从而诱导高血糖的发生，介导糖代谢紊乱性疾病的发生发展。

Claims (4)

1.一种THADA在制备糖代谢紊乱疾病筛选试剂中的应用。
2.根据权利要求1所述的应用，其特征在于，所述疾病包括2型糖尿病、多囊卵巢综合征、肥胖及代谢综合征。
3.根据权利要求1所述的应用，其特征在于，所述应用为将THADA作为靶点或生物标志物制备糖代谢紊乱疾病的筛选制剂。
4.根据权利要求1所述的应用，其特征在于，所述应用包括以THADA作为靶点，检测THADA基因的信使RNA表达水平、转录或转录后修饰水平，或
THADA蛋白表达水平、翻译后修饰水平，或
THADA基因突变、单核苷酸多态性，或
THADA蛋白的功能、定位、活性。
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