Mediators of mitophagy in the regulation of beta cell function

线粒体自噬调节β细胞功能的介质

基本信息

批准号：
9237051
负责人：
Scott Soleimanpour
金额：
$ 38.75万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237051
关键词：
Anabolism Area Autophagosome Beta Cell Binding Bioenergetics Biogenesis Blood Glucose C-terminal Cell physiology Cells Cellular biology Characteristics Chronic Disease Confocal Microscopy Data Defect Diabetes Mellitus Diabetes prevention Diet Disease Ensure Equilibrium Evaluation Failure Financial compensation Functional disorder Genes Genetic Genetic Polymorphism Goals Health Homeostasis Human Impairment Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Lead Lysosomes Mediating Mediator of activation protein Mitochondria Modeling Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Pancreas Pathogenesis Pathway interactions Patients Peripheral Physiological Power Plants Prevention Process Protein Isoforms Proteins Proteomics Publishing RNA Splicing Regulation Reporting Respiration Respiratory physiology Role Sentinel Structure Susceptibility Gene Testing biochemical model blood glucose regulation cell type diabetic fitness insulin secretion islet meetings mitochondrial autophagy mitochondrial dysfunction mouse model novel parkin gene/protein prevent secretion process ubiquitin-protein ligase

项目摘要

ABSTRACT Diabetes results from insufficient functional β-cell mass to meet peripheral insulin demands. β-cells rely upon mitochondrial respiration to generate the energy necessary for insulin biosynthesis, processing, and secretion. Indeed, defects in mitochondrial structure and function have been reported in the β-cells of patients with type 2 diabetes. Defects in mitochondrial structure and function are characteristic of impairments in mitophagy, a selective form of mitophagy necessary for elimination of dysfunctional mitochondria; however, the role of mitophagy in type 2 diabetes pathogenesis is not well understood. We previously discovered a key role for the diabetes susceptibility gene Clec16a in control of glucose homeostasis in humans and mice through its regulation of β-cell mitophagy. Therefore, our goal is to dissect the mechanistic and physiologic regulation of Clec16a-mediated mitophagy in β-cells to elucidate its contribution to diabetes pathogenesis. The central hypothesis to be tested is that disruption of Clec16a regulation of its key effectors, the E3 ubiquitin ligase Nrdp1 and the Nrdp1 target Parkin, contribute to β-cell failure in type 2 diabetes. We will test this hypothesis by the following approach: Specific Aim 1 will directly assess the mechanistic implications of Clec16a disease polymorphisms that alter its functional domains. Specific Aim 2 will determine if the mitophagy initiator Parkin, which recognizes unhealthy mitochondria during mitophagy, serves as the primary downstream effector of Clec16a in β-cell mitophagy. Specific Aim 3 will delineate the role of Clec16a during β-cell compensation for diet-induced obesity and in human islets from type 2 diabetic donors. We anticipate obtaining a clear understanding of the importance and translational relevance of mitophagy in β-cell function from an evaluation of the central effectors crucial to the disposal of unhealthy mitochondria. These results should advance the field of β-cell biology by defining the role of mitophagy in type 2 diabetes pathogenesis and could open new horizons for therapies for patients with diabetes.

抽象的糖尿病是由于功能性β细胞质量不足而导致的，无法满足外周胰岛素需求。 β细胞依靠线粒体呼吸产生胰岛素生物合成，加工和分泌所需的能量。实际上，在2型患者的β细胞中已经报道了线粒体结构和功能的缺陷糖尿病。线粒体结构和功能的缺陷是线粒体损伤的特征消除功能障碍线粒体所需的线粒体的选择性形式；但是， 2型糖尿病发病机理中的线粒体尚不清楚。我们以前发现了糖尿病易感性基因clec16a通过其控制人类和小鼠的葡萄糖稳态控制调节β细胞线粒体。因此，我们的目标是剖析 CLEC16A介导的β细胞线粒体，以阐明其对糖尿病发病机理的贡献。中央要测试的假设是Clec16a其关键作用E3泛素连接酶的破坏 NRDP1和NRDP1靶标蛋白有助于2型糖尿病的β细胞衰竭。我们将通过以下方法：特定目标1将直接评估CLEC16A疾病的机械含义改变其功能域的多态性。特定的目标2将确定线粒体发起者Parkin是否在线粒体期间识别线粒体不健康，是作为主要下游效应子 β细胞线索中的clec16a。特定的目标3将描述Clec16a在β细胞补偿期间的作用饮食引起的肥胖症和2型糖尿病供体的人类胰岛。我们预计会明确通过评估了解线粒体在β细胞功能中的重要性和转化相关性对于处置不健康的线粒体至关重要的中心作用。这些结果应该推进通过定义线粒体在2型糖尿病发病机理中的作用，可以开放新的β细胞生物学领域糖尿病患者治疗的视野。