Alternative complement pathway regulation of beta cell homeostasis

β细胞稳态的替代补体途径调节

• 批准号: 9886859
• 负责人: James C Lo
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-06 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886859
• 关键词: Acute; Alternative Complement Pathway; Antidiabetic Drugs; Architecture; Beta Cell; Biochemical; Biology; Blood Glucose; C3AR1 gene; Cell Count; Cell Death; Cell Maintenance; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic; Chronic Disease; Cleaved cell; Clinical; Cohort Studies; Complement; Complement 3 Convertase; Complement 3a; Complement Activation; Complement Factor D; Complications of Diabetes Mellitus; Cytoprotection; Data; Development; Diabetes Mellitus; Diabetic mouse; Disease; Epidemic; Failure; Foundations; Freedom; Functional disorder; Gene Expression Regulation; Genes; Genetic; Glucose; Goals; Health; Homeostasis; Human; Hyperglycemia; Hypoglycemia; In Vitro; Injections; Insulin; Insulin Resistance; Islet Cell; Islets of Langerhans; Knock-out; Knockout Mice; Light; Link; Metabolic Diseases; Metabolic stress; Molecular; Molecular Mechanisms of Action; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overdose; Pancreas; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phosphoric Monoester Hydrolases; Physiological; Production; Rodent; Role; Serine Protease; Signal Transduction; Stress; Structure of beta Cell of islet; Sulfonylurea Compounds; Testing; Time; Weight Gain; adipokines; analog; blood glucose regulation; cell dedifferentiation; db/db mouse; diabetic; diabetic patient; disease natural history; follow-up; glucagon-like peptide 1; glycemic control; improved; in vivo; insight; insulin secretagogues; insulin secretion; islet; middle age; mouse model; novel; novel therapeutics; premature; prevent; protective effect; receptor; response; transcription factor; transcriptome sequencing

Type 2 diabetes mellitus (T2DM) has become an epidemic. This metabolic disease is marked by insulin resistance in conjunction with progressive loss of beta cell number and function. This relative insulinopenia results from a combination of beta cell dysfunction and loss of beta cell mass. We previously identified the adipokine adipsin, which is reduced in obesity, as a critical regulator of pancreatic beta cell function in murine models of T2DM. Adipsin helps to generate the C3a peptide to effect a signal through its receptor C3aR1 on the beta cell. Our new data show that chronic adipsin treatment of diabetic db/db mice staves off the diabetic complication of beta cell failure. Adipsin downregulates the phosphatase DUSP26 which results in improved beta cell survival. In this proposal, we seek to follow up on these studies and assess the mechanisms behind the protective effects of chronic adipsin treatment. We will pursue the following specific aims: 1. Define the physiological role of the C3aR1 receptor on beta cells using a beta cell specific knockout of C3aR1 in mice. We will determine the requirement of the C3aR1 receptor in maintaining beta cell homeostasis in vivo. 2. Define the role of the phosphatase DUSP26 in regulating beta cell identity and survival. The overall goal of these studies will shed light on how the adipsin/C3a/C3aR1/DUSP26 pathway can be used to maintain long term beta cell health to treat patients with T2DM.

2 型糖尿病 (T2DM) 已成为一种流行病。这种代谢性疾病的特点是胰岛素抵抗以及β细胞数量和功能的逐渐丧失。这种相对胰岛素减少是由于β细胞功能障碍和β细胞质量损失共同导致的。我们之前发现脂肪因子 adipsin 在 T2DM 小鼠模型中是胰腺 β 细胞功能的关键调节因子，在肥胖时脂肪因子会减少。 Adipsin 有助于生成 C3a 肽，通过其受体 C3aR1 在 β 细胞上产生信号。我们的新数据表明，对糖尿病 db/db 小鼠进行长期 Adipsin 治疗可以避免 β 细胞衰竭的糖尿病并发症。 Adipsin 下调磷酸酶 DUSP26，从而提高 β 细胞的存活率。在本提案中，我们寻求跟进这些研究并评估慢性 Adipsin 治疗的保护作用背后的机制。我们将追求以下具体目标： 1. 使用小鼠体内 C3aR1 的 β 细胞特异性敲除来确定 C3aR1 受体对 β 细胞的生理作用。我们将确定 C3aR1 受体维持体内 β 细胞稳态的需求。 2. 定义磷酸酶 DUSP26 在调节 β 细胞身份和存活中的作用。这些研究的总体目标将揭示如何利用 adipsin/C3a/C3aR1/DUSP26 途径维持长期 β 细胞健康以治疗 T2DM 患者。