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：
10343755
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/10343755
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 Persons 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。糖尿病影响全球约3.46亿人。 2004年，估计有340万人死于高血糖的结果。世界卫生组织项目糖尿病将两倍在2005年至2030年之间。两种型糖尿病（T1D）和2型糖尿病（T2D）均由减少人胰腺β细胞量。诊断出高血糖后，仍然存在残留的β细胞在糖尿病患者中检测到。人胰腺β细胞量的再生将提供一种新的方法用于糖尿病治疗。在健康的成年β细胞中，保持速率缓慢。但是，成人胰腺β细胞量在某些情况下（例如肥胖，妊娠等）增加。增强胰腺β细胞增殖的强大方法可以用作治疗糖尿病的新方法患者。可渗透性的化合物为控制细胞增殖提供了方便，有效的方法。化学筛选已应用于鉴定胰腺β细胞扩展的化学诱导剂。但是，很多使用啮齿动物或动物模型鉴定的化合物对主要人类的活动很少或主持人活动胰岛。此外，以前的大多数研究都使用了健康的胰岛样品。尚不清楚是否已确定化合物改善T1D或T2D小岛的增殖。在以前的研究中，我们已经建立了几个化学屏幕平台以识别促进人的产生，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，我们建议将类似于HPSC的Beta样细胞用于筛选促进人胰腺β细胞复制的化合物，并验证已鉴定的使用人类健康，T1D，T2D小岛的化合物。在初步研究中，我们筛选了1,200多种化合物，并确定了可能的命中增加HPSC衍生的胰腺样细胞的增殖。一些热门化合物进一步使用原发性胰岛确认。在这里，我们建议将既定的筛选平台扩展到大型使用随访评估来扩展并确定“化学探针”列表。最后，我们将研究作用机理化学问题。确定的化学问题可直接用于抗糖尿病药物开发或用作发现未来药物发现的新目标的问题。为了实现这些目标，三个目标提出了提出的，包括1）执行高内容屏幕以识别促进人类的化合物胰腺β细胞增殖； 2）执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理。