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。糖尿病影响了全世界大约 3.46 亿人，2004 年估计有 340 万人死于糖尿病。世界卫生组织预测，糖尿病死亡率将增加一倍。 2005 年至 2030 年间。1 型糖尿病 (T1D) 和 2 型糖尿病 (T2D) 都是由于人类胰腺β细胞团在诊断出高血糖后，仍然有残留的β细胞。在糖尿病患者中检测到的人类胰腺β细胞团的再生将提供一种新的方法。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度。胰腺 β 细胞质量在某些情况下会增加，例如肥胖、怀孕等。因此，一种简单且有效的方法增强胰腺β细胞增殖的稳健方法可作为治疗糖尿病的新方法患者。细胞渗透性化合物为控制细胞增殖提供了一种方便有效的方法。筛选已被应用于鉴定胰腺β细胞扩增的化学诱导剂。使用啮齿动物或动物模型鉴定的化合物对原代人类显示出很少或缓和的活性此外，之前的研究大多使用健康的胰岛样本，目前尚不清楚是否已鉴定。在我们之前的研究中，我们已经建立了一些化合物可以改善 T1D 或 T2D 胰岛的增殖。化学筛选平台，用于识别促进人类生成、生存和功能的化合物在这里，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，并验证已识别的化合物使用人类健康、T1D、T2D 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潜在的化合物一些命中化合物进一步增加了 hPSC 来源的胰腺 β 样细胞的增殖。在这里，我们建议将已建立的筛选平台扩展到大型。最后，我们将研究其作用机制。所鉴定的化学探针可直接用于抗糖尿病药物的开发。或用作发现未来药物发现的新靶点的探针为了实现这些目标，需要三个目标。提出了以下建议，包括 1) 进行高内涵筛选，以确定促进人类健康的化合物胰腺β细胞增殖；2) 进行后续测定以最终确定“化学探针”列表；化合物的作用机制。