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A High Content Chemical Screen to Identify the Drug Candidates Promoting Human Beta Cell Proliferation

用于鉴定促进人类β细胞增殖的候选药物的高内涵化学筛选

基本信息

批准号：
10117247
负责人：
Shuibing Chen
金额：
$ 42.38万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117247
关键词：
Adenosine Kinase Adult Affect Agonist Animal Model Antibodies Antidiabetic Drugs Beta Cell Biochemical Genetics Biological Assay Blood Glucose Cadaver Cell Proliferation Cell physiology Cells Cessation of life Chemical Actions Chemicals Childhood Clinical Trials DNA biosynthesis Diabetes Mellitus Diagnosis FDA approved Future Generations Goals Hormones Human Hyperglycemia Insulin Insulin-Dependent Diabetes Mellitus Methods Mitosis Modeling Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Obesity Pancreas Patients Permeability Pharmaceutical Preparations Phenotype Physiological Pregnancy Reporting Residual state Rodent Model Safety Sampling Signal Pathway Signal Transduction Stains Structure of beta Cell of islet Testing Variant Vigabatrin Work World Health Organization cheminformatics cytotoxicity diabetes mellitus therapy drug candidate drug development drug discovery fluorophore follow-up glycogen synthase kinase 3 beta inhibitor human pluripotent stem cell improved innovation islet kinase inhibitor novel novel strategies screening small molecule libraries type I and type II diabetes

项目摘要

Abstract. Diabetes affects approximately 346 million people worldwide. In 2004, an estimated 3.4 million people died from the consequence of high blood glucose. The World Health Organization projects that diabetes death will double between 2005 and 2030. Both type 1 diabetes (T1D) and type 2 diabetes (T2D) result from the decrease of human pancreatic beta cell mass. After the diagnosis of high blood glucose, there are still residual beta cells detected in diabetes patients. The regeneration of human pancreatic beta cell mass will provide a novel approach for diabetes therapy. In healthy adult beta cell mass is maintained at a slow proliferation rate. However, adult pancreatic beta cell mass increases in certain conditions, such as obesity, pregnancy, etc. Thus, an easy and robust method to enhance pancreatic beta cell proliferation can be used as a new approach to treat diabetes patients. Cell-permeable compounds provide a convenient and efficient approach to control cell proliferation. Chemical screens have been applied to identify chemical inducers of pancreatic beta cell expansion. However, many compounds identified using rodents or animal models show little or moderator activities on primary human islets. In addition, most of the previous studies used healthy islet samples. It is not clear whether the identified compounds improve proliferation of T1D or T2D islets. In our previous studies, we have established several chemical screen platforms to identify the compounds promoting the generation, survival and function of human pluripotent stem cell (hPSC)-derived beta-like cells. Here, we propose to use hPSC-derived beta-like cells to screen for compounds that promote human pancreatic beta cell replication, and to validate the identified compounds using human healthy, T1D, T2D islets. In the preliminary studies, we have screened more than 1,200 compounds and identified hits that potentially increase the proliferation of hPSC-derived pancreatic beta-like cells. Some of hit compounds were further confirmed using primary human islets. Here, we proposed to expand the established screening platform to large scale and identify a list of “chemical probe” using follow-up assays. Finally, we will study the mechanism of action of the chemical probes. The identified chemical probes can be directly used for anti-diabetes drug development or be used as the probes to discover novel targets for future drug discovery. To reach these goals, three aims were proposed, including 1) Carry out a high content screen to identify the compounds promoting human pancreatic beta cell proliferation; 2) Perform follow-up assays to finalize the “chemical probe” list; 3) Study the mechanism of action of the compounds.

抽象的。糖尿病影响着全世界约3.46亿人。2004年，估计有340万人死于高血糖的后果。世界卫生组织预测，糖尿病死亡人数将增加一倍，在2005年到2030年之间。1型糖尿病（T1 D）和2型糖尿病（T2 D）都是由于糖尿病患者体内胰岛素水平的降低而引起的。人胰腺β细胞团。高血糖确诊后，仍有β细胞残留在糖尿病患者中检测到。人胰腺β细胞团的再生将提供一种新的途径用于糖尿病治疗。在健康成人中，β细胞群维持在缓慢的增殖速率。然而，成人胰腺β细胞质量在某些情况下增加，例如肥胖、怀孕等。增强胰腺β细胞增殖的稳健方法可用作治疗糖尿病的新方法患者细胞渗透性化合物提供了控制细胞增殖的方便和有效的方法。化学已经应用筛选来鉴定胰腺β细胞扩增的化学诱导剂。但不少使用啮齿类动物或动物模型鉴定的化合物显示出对初级人类的很少或缓和活性。小岛此外，大多数先前的研究使用健康的胰岛样本。目前尚不清楚是否确定化合物改善T1 D或T2 D胰岛的增殖。在我们以前的研究中，我们已经建立了几个化学筛选平台，以确定促进人类生殖，生存和功能的化合物多能干细胞（hPSC）衍生的β样细胞。在这里，我们建议使用hPSC衍生的β样细胞，筛选促进人胰腺β细胞复制的化合物，并验证所鉴定的使用人类健康的T1 D、T2 D胰岛的化合物。在初步研究中，我们筛选了1,200多种化合物，并确定了可能增加hPSC衍生的胰腺β样细胞的增殖。一些命中化合物进一步使用原代人类胰岛证实。在此，我们建议将已建立的筛选平台扩大到大型使用后续分析来缩放和识别“化学探针”列表。最后，我们将研究其作用机制化学探测器。所鉴定的化学探针可直接用于抗糖尿病药物的开发或用作探针以发现未来药物发现的新靶点。为了实现这些目标，有三个目标。提出了包括1）进行高内容筛选，以识别促进人体健康的化合物胰腺β细胞增殖; 2）进行后续测定以最终确定“化学探针”列表; 3）研究化合物的作用机制。