A High Throughput Screening to Identify Compounds Rescuing Human Pancreatic Beta Cell Function in Diabetic Conditions

高通量筛选以鉴定在糖尿病患者中拯救人类胰腺 β 细胞功能的化合物

基本信息

批准号：
9905514
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：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905514
关键词：
Acetylcysteine Affect Antidiabetic Drugs Antioxidants Beta Cell Biochemical Biological Assay Blood Glucose Cause of Death Cell Death Cell Line Cell Proliferation Cell physiology Cells Chemical Actions Chemicals Chronic Disease Defect Development Diabetes Mellitus Disease Enzyme-Linked Immunosorbent Assay Exposure to Fatty Acids Follow-Up Studies Functional disorder Future Glucose Goals High Fat Diet Human Hyperglycemia Impairment In Vitro Individual Insulin Resistance Libraries Luciferases Metabolic Modeling Monitor Non-Insulin-Dependent Diabetes Mellitus Oleates Organ Pathogenesis Pharmaceutical Preparations Population Proinsulin Rattus Reporter Rodent Signal Transduction Structure of beta Cell of islet Structure-Activity Relationship Study models Testing Time Variant Work World Health Organization base biophysical techniques cell growth regulation cheminformatics cytotoxicity diabetic drug development drug discovery follow-up high throughput screening humanized mouse imaging modality improved in vivo insulin secretion insulinoma islet lead optimization luminescence mouse model nano nanoluciferase new therapeutic target novel screening small molecule small molecule libraries

Acetylcysteine Affect Antidiabetic Drugs Antioxidants Beta Cell Biochemical Biological Assay Blood Glucose Cause of Death Cell Death Cell Line Cell Proliferation Cell physiology Cells Chemical Actions Chemicals Chronic Disease Defect Development Diabetes Mellitus Disease Enzyme-Linked Immunosorbent Assay Exposure to Fatty Acids Follow-Up Studies Functional disorder Future Glucose Goals High Fat Diet Human Hyperglycemia Impairment In Vitro Individual Insulin Resistance Libraries Luciferases Metabolic Modeling Monitor Non-Insulin-Dependent Diabetes Mellitus Oleates Organ Pathogenesis Pharmaceutical Preparations Population Proinsulin Rattus Reporter Rodent Signal Transduction Structure of beta Cell of islet Structure-Activity Relationship Study models Testing Time Variant Work World Health Organization base biophysical techniques cell growth regulation cheminformatics cytotoxicity diabetic drug development drug discovery follow-up high throughput screening humanized mouse imaging modality improved in vivo insulin secretion insulinoma islet lead optimization luminescence mouse model nano nanoluciferase new therapeutic target novel screening small molecule small molecule libraries

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项目摘要

Abstract Diabetes is a polygenetic and chronic disease affecting approximately 346 million people worldwide. In 2004, an estimated 3.4 million people died from the consequences of high blood glucose. The World Health Organization projects that deaths caused by diabetes will double between 2005 and 2030. Uncontrolled diabetes results in hyperglycemia, which over time leads to serious damage to many organs. More than 90% of the diabetic population has type 2 diabetes mellitus (T2DM). The classic pathogenesis of T2DM involves insulin resistance and pancreatic beta cell dysfunction, marked by impaired, glucose-stimulated insulin secretion. Only 40-50% of individuals with insulin resistance progress to T2DM. The pivotal defect in those who progress is that pancreatic beta cells fail to compensate for insulin resistance, become dysfunctional, and eventually die. Thus, pancreatic beta cell dysfunction is a key step in the progression from metabolic impairments to a disease state. Most of the current efforts on anti-diabetes drug discovery focus on either protecting pancreatic beta cells from cell death or inducing beta cell proliferation. Only a few drugs have been developed to improve pancreatic beta cell function. It is well known that the same compound may have opposite effects on healthy and diseased cells, since different mechanisms may be involved in the regulation of cellular physiology versus pathophysiology. Therefore, a critical gap in anti-diabetes drug discovery is the lack of drugs rescuing human beta cell function in a diabetic condition. This deficit is mainly due to the lack of a high-throughput screening (HTS) platform to directly monitor human pancreatic beta cell function. In our preliminary studies, we created a luminescence-based HTS assay to identify compounds that rescue human pancreatic beta cell function in a diabetic condition. After completing a pilot screen using a library with more than 2,000 small molecules, we identified hit compounds that potentially rescue the impaired, glucose- stimulated insulin secretion of human pancreatic beta cells exposed to glucolipotoxicity. Here, we propose to perform a large-scale HTS using our established platform on multiple chemical libraries containing ~240,000 compounds, validate the hit compounds using follow-up assays, optimize lead compounds through simple structure activity relationship analyses, and evaluate the function of the identified chemical probes in diabetic-humanized mouse models. Finally, we will perform target identification and study the mechanism of action of the chemical probes. The identified chemical probes can be directly used for anti-diabetes drug development or serve to discover novel disease targets for future drug discovery.

抽象的糖尿病是一种多基因和慢性疾病，影响了全球约3.46亿人。 2004年，一个估计有340万人死于高血糖的后果。世界卫生组织糖尿病造成的死亡的项目将在2005年至2030年之间翻一番。不受控制的糖尿病会导致高血糖，随着时间的流逝会导致许多器官损害。超过90％的糖尿病患者人口患有2型糖尿病（T2DM）。 T2DM的经典发病机理涉及胰岛素抵抗和胰腺β细胞功能障碍，标志着受损，葡萄糖刺激的胰岛素分泌。只有40-50％具有胰岛素抵抗的个体向T2DM进展。那些进步的人的关键缺陷是胰腺 β细胞无法补偿胰岛素抵抗，发病障碍并最终死亡。因此，胰腺 β细胞功能障碍是从代谢障碍到疾病状态的发展的关键步骤。目前，大多数关于抗糖尿病药物发现的努力都集中在保护胰腺β细胞免于细胞死亡或诱导β细胞增殖。仅开发了一些药物来改善胰腺β 细胞功能。众所周知，同一化合物可能对健康和患病细胞有相反的影响，由于可能参与细胞生理学与病理生理学的调节可能涉及不同的机制。因此，抗糖尿病药物发现的关键差距是缺乏营救人β细胞的药物在糖尿病状态下的功能。这种赤字主要是由于缺乏高通量筛查（HTS）平台直接监视人类胰腺β细胞功能。在我们的初步研究中，我们创建了一个基于发光的HTS分析，以识别营救的化合物人胰腺β细胞在糖尿病状态下的功能。在使用库一起完成试验屏幕之后我们确定了2,000多个小分子，确定了可能挽救受损的葡萄糖的命中化合物刺激的胰岛素分泌，暴露于糖脂肪毒性的人胰腺β细胞。在这里，我们建议使用我们已建立的平台在包含多个化学库上进行大规模的HTS 〜240,000种化合物，使用后续分析验证HIT化合物，通过简单的结构活动关系分析，并评估已鉴定的化学探针的功能糖尿病人类化的小鼠模型。最后，我们将执行目标识别并研究化学探针的作用。确定的化学探针可直接用于抗糖尿病药物开发或为未来的药物发现发现新的疾病靶标。