CN104826131B - gene cluster miR-17-92 in the manufacture of a medicament the treatment of mental diseases - Google Patents

gene cluster miR-17-92 in the manufacture of a medicament the treatment of mental diseases Download PDF

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CN104826131B
CN104826131B CN201510179139.1A CN201510179139A CN104826131B CN 104826131 B CN104826131 B CN 104826131B CN 201510179139 A CN201510179139 A CN 201510179139A CN 104826131 B CN104826131 B CN 104826131B
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anxiety
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孙涛
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涛康生物科技(上海)有限公司
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Abstract

本发明涉及种药物技术领域的miR‑17‑92基因簇在制备治疗精神类疾病药物中的用途。 The present invention relates to the field of pharmaceutical techniques of gene cluster miR-17-92 in the manufacture of a medicament the treatment of mental diseases. 本发明对于基础研究和进步的临床应用具有现实意义,通过miR‑17‑92,研究者能探测到对抗抑郁药有应答效果的新的蛋白质编码基因和非编码miRNAs;本发明将拓展相关的研究视野,为将来开发新型抗抑郁药物打下良好的基础;本发明将开拓新的抗抑郁治疗靶点,由于miRNA是小分子,极易体外合成和导入细胞内,操纵体内miRNA表达量越来越成为可能。 The invention has practical significance for basic research and clinical applications progress through miR-17-92, researchers can detect that there is a response effect of antidepressants on new protein-coding genes and non-coding miRNAs; related research will expand the present invention field of view, for the future development laid a good foundation of new antidepressants; the present invention is to develop a new antidepressant therapeutic target, since the miRNA molecule is a small, easily synthesized and introduced into a cell in vitro, in vivo manipulation of miRNA expression has become increasingly may.

Description

mi R-17-92基因簇在制备治疗精神类疾病药物中的用途 mi R-17-92 gene cluster for the manufacture of a medicament the treatment of mental diseases

技术领域 FIELD

[0001]本发明涉及药物技术领域,具体涉及一种miR-17-92基因簇在制备治疗精神类疾病药物中的用途。 [0001] The present invention relates to the field of pharmaceutical technology, in particular to a gene cluster miR-17-92 in the manufacture of a medicament the treatment of mental diseases.

背景技术 Background technique

[0002]由于遗传,环境及现代生活的快节奏和压力,情绪性相关病症(mood disorders) 越发突现。 [0002] As the fast pace and stress of genetic, environmental and modern life, mood-related disorders (mood disorders) more fulfilled. 在中国,抑郁症的发病率为3%_5%,抑郁症患者估计有3000万人。 In China, the incidence of depression rate of 3% _5% of patients with depression have an estimated 30 million people. 仅河北、浙江等几个省的调查显示,焦虑症的患病率在5 %-7 %。 Only survey Hebei, Zhejiang and other provinces showed that the prevalence of anxiety disorders in 5% -7%. 但由于在中国患者就诊率低,焦虑和抑郁患者的数目可能比统计的更高。 However, due to the low rate of treatment patients in China, the number of patients with anxiety and depression may be higher than the statistics. 在美国每年有4千万成年人受着焦虑障碍的影响。 There affecting 40 million adults suffering from anxiety disorders each year in the United States. 病人在经历长期的焦虑带来的恐惧和无助后,很可能产生严重的情绪失控,比如自杀倾向。 Patient after experiencing fear and anxiety caused by long-term helpless, is likely to have serious emotional control, such as suicidal tendencies. 世界各国在焦虑和抑郁患者上花费了大量财政支出,成为了社会的一大经济负担。 Countries in the world spend a lot of expenditure on anxiety and depression, it has become a major economic burden on society.

[0003] 临床上焦虑与抑郁症有大量共病症状(comorbidity)。 [0003] clinical anxiety and depression have a large number of co-morbid symptoms (comorbidity). 服用抗抑郁药物是一种有效治疗手段。 Antidepressant medication is an effective treatment. 三环类抗抑郁药丙咪嗪(imipramine)和选择性5羟色胺再摄取抑制剂(selective serotonin re-uptake inhibitors,SSRI)氣西汀(fluoxetine),京尤是两类用于治疗抑郁或焦虑的药物。 Tricyclic antidepressant imipramine (imipramine) and selective serotonin reuptake inhibitors (selective serotonin re-uptake inhibitors, SSRI) paroxetine gas (fluoxetine), especially in Beijing is two for treating depression or anxiety drug. 但抗抑郁药物并不对所有患者有效。 But antidepressants are not effective in all patients. 这些心理障碍疾病的病理机制,及抗抑郁药物作用靶点的分子机理仍不明晓。 These pathological mechanisms of mental disorders, and the molecular mechanism of antidepressant drug targets still unknown dawn. 因此,开展焦虑抑郁症状分子机理的研究,及开发全新抗焦虑抑郁药物和治疗手段,是这个研究领域当下工作之重。 Therefore, research the molecular mechanism of depressive symptoms of anxiety, depression and anti-anxiety drugs and develop new treatment, this is heavy work of contemporary research.

[0004] 微型RNA (micr〇RNA,miRNA)的发现,使人们得以从基因调控的水平,用新的角度研究大脑发育和成熟的机制。 [0004] Micro RNA (micr〇RNA, miRNAs) is found from the level of gene made it possible to control, in a new way research brain development and maturation mechanisms. miRNA是一类由22个核苷酸组成的内源性非编码小RNA。 miRNA are a class of endogenous small non-coding RNA of 22 nucleotides. 通过RNAase III一Dicer的酶切作用,miRNA前体被加工为成熟miRNAs。 Action of a cleavage by RNAase III of Dicer, miRNA precursor is processed into mature miRNAs. 成熟miRNA能够识别他的靶标信使RNA (messenger RNA,mRNA),并结合到靶标信使RNA的3'非编码区(3' untranslated region,3' UTR)。 Mature miRNA can identify his target messenger RNA (messenger RNA, mRNA), and coupled to the 3 'untranslated region (3' target messenger RNA untranslated region, 3 'UTR). 从而降低该mRNA稳定性,或阻断mRNA的翻译。 Thereby reducing the stability of mRNA, or blocking translation of mRNA. 人们发现一些焦虑患者大脑内miRNA表达量方生改变,但具体哪些miRNA在焦虑和抑郁症中起作用,以及对抗抑郁药物发生反应,我们仍不知晓。 It was found that some of the anxiety within the brains of patients miRNA expression is life changing, but what specific miRNA in anxiety and depression play a role, as well as reactions to antidepressant drugs, we still do not know.

发明内容 SUMMARY

[0005] 本发明的目的在于克服现有技术的不足,提供一种微型RNAmiR-17-92作为焦虑和抑郁症诊断及治疗的新靶标。 [0005] The object of the present invention is to overcome the disadvantages of the prior art, to provide a miniature RNAmiR-17-92 as a new target for anxiety and depression, diagnosis and treatment. 本申请的发明人经过研究,证实一个微型RNA—miR-17-92对抗抑郁药物起反应,并可以作为焦虑和抑郁症诊断及治疗的新靶标。 The inventor of the present application through research, confirmed that a micro RNA-miR-17-92 react to antidepressant medication, and can serve as a new target for anxiety and depression diagnosis and treatment. miR-17-92基因家族包含的主要基因RNA序列为:mi R-17,caaagugcuuacagugcagguag;miR_19, ugugcaaaucuaugcaaaacuga;miR—92,agguugggauuugucgcaaugcu 〇 The main gene RNA sequence miR-17-92 gene family comprising of: mi R-17, caaagugcuuacagugcagguag; miR_19, ugugcaaaucuaugcaaaacuga; miR-92, agguugggauuugucgcaaugcu square

[0006] 本发明是通过以下的技术方案实现的,本发明涉及一种miR-17-92基因簇在制备治疗精神类疾病药物中的用途。 [0006] The present invention is achieved by the following technical solution, the present invention relates to a gene cluster miR-17-92 in the manufacture of a medicament the treatment of mental diseases.

[0007] 优选地,所述精神类疾病为抑郁症或焦虑症。 [0007] Preferably, the mental disorder is depression or anxiety.

[0008] 优选地,所述miR-17-92基因簇包含以下组合中的一种或几种:miR-17,miR-19,m iR-92〇 [0008] Preferably, the miR-17-92 gene cluster comprising one or several of the following combinations: miR-17, miR-19, m iR-92〇

[0009] 优选地,所述miR-17 的序列为caaagugcuuacagugcagguag。 [0009] Preferably, the miR-17 sequence is caaagugcuuacagugcagguag.

[0010] 优选地,所述miR-19的序列为ugugcaaaucuaugcaaaacug。 [0010] Preferably, the miR-19 sequence is ugugcaaaucuaugcaaaacug.

[0011] 优选地,所述miR-92 的序列为agguugggauuugucgcaaugcu 〇 [0011] Preferably, the sequence of miR-92 billion agguugggauuugucgcaaugcu

[0012] 优选地,所述应用具体为:提升miR-17-92基因簇的表达量,进而提升抗抑郁能力。 [0012] Preferably, the specific application is: to enhance the expression of miR-17-92 cluster gene, thereby enhancing the ability antidepressant.

[0013] 优选地,所述应用具体为:提升miR-17-92基因簇的表达量,进而提升抗焦虑能力。 [0013] Preferably, the specific application is: to enhance the expression of miR-17-92 cluster of genes, and thus enhance the anxiolytic potential.

[0014] 优选地,所述应用具体为:提升miR-17-92基因簇的表达量,进而同时提升抗焦虑和抗抑郁能力。 [0014] Preferably, the specific application is: to enhance the expression of miR-17-92 cluster of genes, and thus enhance the ability to simultaneously anxiolytic and antidepressant.

[0015] 优选地,所述应用具体为:所述miR-17-92基因簇作为制备诊断抑郁症、或诊断焦虑症,或同时诊断抑郁症和焦虑症的靶标药物中的应用。 [0015] Preferably, the application is specifically: the miR-17-92 cluster manufacture of a gene diagnosis of depression, anxiety disorder or diagnosis, or the simultaneous diagnosis of depression and anxiety, as the target drug.

[0016] 与现有技术相比,本发明具有如下的有益效果:由于抑郁和焦虑障碍有很多共病症,临床常用抗抑郁疗法来治疗焦虑。 [0016] Compared with the prior art, the present invention has the following advantages: Since there are a lot of depression and anxiety disorders comorbidity, clinical antidepressant therapy used to treat anxiety. 然而,现有的药物临床上仍对部分病人施治无效。 However, the existing clinical drug still has no effect on some patients and treatment. 尤其是抗抑郁药与其作用靶标在分子水平的应答机制,仍鲜为人知。 Especially its antidepressant action target response mechanisms at the molecular level, still little known. 焦虑和抑郁症状,给患者带来了巨大的精神压力和躯体不适。 Anxiety and depression symptoms, the patient tremendous mental stress and physical discomfort. 超过25%的焦虑症患者,终身都无法得到治愈。 More than 25% of patients with anxiety disorders, life can not be cured. 本发明对于基础研究和进一步的临床应用具有现实意义。 The invention has practical significance for further basic research and clinical application. 通过miR-17-92,研究者能探测到对抗抑郁药有应答效果的新的蛋白质编码基因和非编码miRNAs;本发明将拓展相关的研究视野, 为将来开发新型抗抑郁药物打好基础。 By miR-17-92, researchers can detect that there is a response effect of antidepressants on new protein-coding genes and non-coding miRNAs; The invention will expand research horizons related to lay the foundation for the future development of new antidepressant drugs. 进一步地,本发明将开拓新的抗抑郁治疗靶点,由于miRNA是小分子,极易体外合成和导入细胞内,操纵体内miRNA表达量越来越成为可能。 Further, the present invention is to develop a new antidepressant therapeutic target, since the miRNA molecule is a small, easily synthesized and introduced into a cell in vitro, in vivo manipulation of the expression of miRNA increasingly possible. 因此,miRNA日渐成为人类神经系统疾病的基因治疗新工具。 Therefore, miRNA gene therapy is becoming a disease of the nervous system and new tools. 用miRNA作为抗抑郁抗焦虑的新型治疗靶标,亦是前景光明。 MiRNA as an antidepressant with anxiolytic new therapeutic targets, is also promising.

附图说明 BRIEF DESCRIPTION

[0017] 通过阅读参照以下附图对非限制性实施例所作的详细描述,本发明的其它特征、 目的和优点将会变得更明显: [0017] By reading the following detailed description of non-limiting embodiments given with reference to the following figures, other features of the present invention, objects and advantages will become more apparent:

[0018] 图1.在压力诱导的焦虑实验中,压力促使miR-17-92表达水平降低。 [0018] Figure 1. Experimental stress-induced anxiety, the pressure causes the level of decreased expression of miR-17-92. 相反,在小鼠服用抗抑郁药后,miR-17-92的表达得以回升。 In contrast, antidepressants in mice, expression of miR-17-92 is picked up.

[0019] 图2.在Morris水迷宫实验中,相比野生型(wild-type,WT),miR-17_92条件性敲除小鼠(KO)并未表现显著性的学习和记忆功能减退。 [0019] Figure 2. Morris water maze test, as compared to the wild-type (wild-type, WT), miR-17_92 conditional knockout mice (KO) did not show significant learning and memory dysfunction.

[0020] 图3·在旷场实验(open field)中,与野生型(wild-type,WT)小鼠相比,miR-17-92 条件性敲除鼠(KO)有显著性的焦虑倾向;n>10,: p〈0.01。 [0020] FIG. 3. In the open field test (open field) compared to the wild-type (wild-type, WT) mice, miR-17-92 conditional knockout mice (KO) had significant anxiety tends addition ; n> 10 ,: p <0.01.

具体实施方式 Detailed ways

[0021] 下面结合具体实施例,进一步阐述本发明。 [0021] The following embodiments with reference to specific embodiments, further illustrate the present invention. 应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。 It should be understood that these embodiments are illustrative only and the present invention is not intended to limit the scope of the invention. 下列实施例中未注明具体条件的试验方法,通常按照常规条件,例如萨姆布鲁克等分子克隆:实验手册第三版(科学出版社,2002)中所述的条件,或者按照各制造商所建议的条件。 Test Method no specific conditions in the examples below, are performed under routine conditions, for example, Sambrook et Molecular Cloning: A Laboratory Manual, Third Edition (Academic Press, 2002) in the conditions according to the respective manufacturers or It recommended conditions.

[0022] 实施例1 [0022] Example 1

[0023] 发表的研究指出,长期压力可以诱发小鼠产生焦虑症。 Studies [0023] published pointed out that chronic stress can induce anxiety in mice. 申请人首先验证了压力引起的焦虑是否和miR-17-92在大脑中的表达水平有关。 The applicant first verify whether the stress-induced anxiety and miR-17-92 expression levels in the brain related. 在将第十周龄C57/BL6小鼠置于狭小空间两周后,诱发了小鼠的焦虑。 After the tenth week old C57 / BL6 mice were placed in a small space for two weeks, the mice induced anxiety. 申请人提取了大脑海马区的RNA,发现miR-17-92的表达显著降低(图1)。 Applicants extracted the RNA of hippocampus, expression of miR-17-92 was found significantly decreased (FIG. 1). 这说明压力引起的焦虑可以降低miR-17-92的表达。 This shows that stress-induced anxiety can decrease the expression of miR-17-92. 进一步的,选择性5羟色胺再摄取抑制剂(selective serotonin re-uptake inhibitors,SSRI)氣西汀(fluoxetine)是目前常用的抗抑郁药。 Further, a selective serotonin reuptake inhibitor (selective serotonin re-uptake inhibitors, SSRI) gas paroxetine (as fluoxetine) are currently used antidepressants. 申请人在给第十周龄的小鼠施与压力的同时,喂服了氟西汀。 Applicant administered at a tenth week-old mice pressure while feeding served fluoxetine. 申请人发现抗抑郁药的使用可以使小鼠大脑海马区miR-17-92的表达量显著回升(图1)。 Applicant has found that antidepressants can cause the mouse brain The expression of miR-17-92 significant rebound hippocampus (FIG. 1). 这说明miR-17-92对抗抑郁药起作用。 This shows that the miR-17-92 antidepressants work.

[0024] 实施例2 [0024] Example 2

[0025] 为了研究miR-17-92的具体功能,申请人繁育了miR-17-92条件性敲除小鼠(knockout,K0)。 [0025] In order to specifically study the function of miR-17-92, miR-17-92 applicant bred conditional knockout mice (knockout, K0). 在Nestin-CreERtm小鼠和fIoxed的miR-17-92转基因小鼠交配后,只有在注射他莫昔芬(Tamoxifen)条件下,才能诱导Cre活性,以敲除miR-17-92在成年大脑海马区的表达。 In mice and Nestin-CreERtm fIoxed of miR-17-92 mating transgenic mice, only the injection tamoxifen (of Tamoxifen) conditions, in order to induce the activity of Cre to knock miR-17-92, except in the adult brain hippocampus expression area. 这个条件性敲除小鼠,称作miR-17-92K0。 The conditional knockout mice, referred to as miR-17-92K0. 在小鼠第五周龄时,对其连续5天注射了Tamoxifen,以激活Cre活性,敲除miR-17-92的表达。 When the fifth week old mice, injected them 5 days of Tamoxifen, to activate the activity of Cre, knockdown of the expression of miR-17-92. 在小鼠第九周龄时,申请人利用经典的Morris水迷宫实验,对该小鼠的学习记忆能力状况进行了检测。 In the ninth week old mice, the applicant using classical Morris water maze learning and memory ability of the mice were tested conditions. 将小鼠置于一个直径1米的圆形水迷宫中。 The mice were placed in a circular water maze 1 meter in diameter. 在水迷宫中隐藏着一个平台,通过测试小鼠发现平台的时间,可以推测小鼠学习和记忆的能力。 A hidden platform in a water maze, found time platform by testing in mice, the mice learning and memory capacity can be inferred. 申请人发现miR-17-92条件性敲除鼠并未在实验中表现显著性的学习和记忆功能减退(图2)。 Applicants have found that miR-17-92 conditional knockout mice did not show significant learning and memory dysfunction (Figure 2) in the experiment. 我们的结果表明,miR-17-92基因敲除,并不影响小鼠正常的学习记忆功能。 Our results show that, miR-17-92 gene knockout, does not affect the normal learning and memory in mice.

[0026] 实施例3 [0026] Example 3

[0027] 令人吃惊的是,申请人发现,敲除miR-17-92基因导致小鼠产生类似焦虑症和抑郁的行为(图3)。 [0027] Surprisingly, applicants discovered that miR-17-92 gene knockout mice produced similar results in anxiety and depressive behavior (FIG. 3). 在旷场实验(open field)中,将小鼠置于50cm X 50cm的开放空间中。 In the open field test (open field), the mice were placed in 50cm X 50cm of open space. 由于小鼠比较害怕暴漏于开放空间和光照之下,小鼠越是焦虑,就会越躲避开放空间和光照。 Since more afraid of mice storm drain beneath the open space and light, the mice more anxious to avoid the more open space and light. 因此,我们可以通过测试小鼠在开放空间停留的时间,爬行的距离,判断小鼠的焦虑程度。 Therefore, we can pass the test mice at the time of the open space to stay, crawling distance to determine the degree of anxiety in mice. 申请人的结果显示,miR-17-92敲除小鼠很少停留在旷场中心,说明降低miR-17-92在大脑中的表达,导致小鼠呈现增高的焦虑症状(图3)。 The results show the applicant, miR-17-92 knockout mice rarely stay in the center of the open field, indicating decreased expression of miR-17-92 in the brain, resulting in increased anxiety in mice rendered (FIG. 3). 这说明miR-17-92可以作为焦虑和抑郁症的新的病理标记物。 This shows that the miR-17-92 can be used as a new marker for pathological anxiety and depression.

[0028] 综上所述,由于抑郁和焦虑障碍有很多共病症,临床常用抗抑郁疗法来治疗焦虑。 [0028] In summary, since there are a lot of depression and anxiety disorders comorbid conditions, commonly used in clinical antidepressant therapies to treat anxiety. 然而,现有的药物临床上仍对部分病人施治无效。 However, the existing clinical drug still has no effect on some patients and treatment. 尤其是抗抑郁药与其作用靶标在分子水平的应答机制,仍鲜为人知。 Especially its antidepressant action target response mechanisms at the molecular level, still little known. 焦虑和抑郁症状,给患者带来了巨大的精神压力和躯体不适。 Anxiety and depression symptoms, the patient tremendous mental stress and physical discomfort. 超过25%的焦虑症患者,终身都无法得到治愈。 More than 25% of patients with anxiety disorders, life can not be cured. 本发明对于基础研究和进一步的临床应用具有现实意义。 The invention has practical significance for further basic research and clinical application. 通过miR-17-92,研究者能探测到对抗抑郁药有应答效果的新的蛋白质编码基因和非编码miRNAs。 By miR-17-92, researchers can detect responsive antidepressant effect on new protein-coding genes and non-coding miRNAs. 这将拓展研究视野,为将来开发新型抗抑郁药物打好基础。 This will expand research horizons, lay the foundation for the future development of new antidepressant drugs. 进一步地,本专利将开拓新的抗抑郁治疗革巴点,由于miRNA是小分子,极易体外合成和导入细胞内, 操纵体内miRNA表达量越来越成为可能。 Further, the present patent is to develop a new antidepressant Gerba point, since the miRNA molecule is a small, easily synthesized and introduced into a cell in vitro, in vivo manipulation of the expression of miRNA increasingly possible. 因此,miRNA日渐成为人类神经系统疾病的基因治疗新工具。 Therefore, miRNA gene therapy is becoming a disease of the nervous system and new tools. 用miRNA作为抗抑郁抗焦虑的新型治疗靶标,亦是前景光明。 MiRNA as an antidepressant with anxiolytic new therapeutic targets, is also promising.

[0029] 以上对本发明的具体实施例进行了描述。 [0029] The foregoing specific embodiments of the invention have been described. 需要理解的是,本发明并不局限于上述特定实施方式,本领域技术人员可以在权利要求的范围内做出各种变形或修改,这并不影响本发明的实质内容。 Is to be understood that the present invention is not limited to the particular embodiments, those skilled in the art can make various changes and modifications within the scope of the appended claims, this does not affect the substance of the present invention.

Claims (4)

1. 一种miR-17-92基因簇的检测试剂在制备诊断精神类疾病试剂中的用途;所述miR-17-92基因簇由以下基因组成:miR-17, miR-19,miR-92; 所述精神类疾病为焦虑症;患者体内miR-17-92基因簇的表达量下降。 A miR-17-92 cluster gene detection reagent in the preparation of the diagnostic reagent of mental diseases; the miR-17-92 gene cluster consisting of the following genes: miR-17, miR-19, miR-92 ; the mental disorder is anxiety disorder; expression of the gene in the patient miR-17-92 cluster is lowered.
2. 根据权利要求1所述miR-17-92基因簇的检测试剂在制备诊断精神类疾病药物中的用途,其特征在于,所述miR-17的序列为caaagugcuuacagugcagguag。 The detection reagent of the gene cluster 1 miR-17-92 for the preparation of a medicament for the diagnosis of mental illness claim, wherein the miR-17 sequence is caaagugcuuacagugcagguag.
3. 根据权利要求1所述miR-17-92基因簇的检测试剂在制备诊断精神类疾病药物中的用途,其特征在于,所述miR-19的序列为ugugcaaaucuaugcaaaacug。 The detection reagent of the gene cluster 1 miR-17-92 for the preparation of a medicament for the diagnosis of mental illness claim, wherein the miR-19 sequence is ugugcaaaucuaugcaaaacug.
4. 根据权利要求1所述miR-17-92基因簇的检测试剂在制备诊断精神类疾病药物中的用途,其特征在于,所述miR-92的序列为agguugggauuugucgcaaugcu 〇 The detection reagent of the gene cluster 1 miR-17-92 for the preparation of a medicament for the diagnosis of mental illness claim, wherein the miR-92 sequence of square agguugggauuugucgcaaugcu
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WO2009004632A2 (en) * 2007-07-05 2009-01-08 Yeda Research And Development Co. Ltd. Methods of identifying components of a biological pathway and use of said components in regulating diseases associated with altered cell proliferation
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WO2009004632A2 (en) * 2007-07-05 2009-01-08 Yeda Research And Development Co. Ltd. Methods of identifying components of a biological pathway and use of said components in regulating diseases associated with altered cell proliferation
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