Dynamin function in pancreatic beta-cell autophagy

胰腺 β 细胞自噬中的动力功能

基本信息

批准号：
10693338
负责人：
Xuelin Lou
金额：
$ 39万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-30 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693338
关键词：
Acetylation Affect American Animals Autophagocytosis Beta Cell Binding Biochemical Biochemistry Biological Assay Cell Line Cell physiology Cellular biology Chronic Cytoprotection Data Defect Development Diabetes Mellitus Diet Dynamin Dynamin 2 Dynamin III Eating Endocytosis Epidemic Failure Fasting Genes Genetic Genetic Models Guanosine Triphosphate Phosphohydrolases Image Imaging Techniques Impairment In Vitro Insulin Investments Knowledge Lead Lysosomes Mediating Membrane Metabolic stress Methodology Methods Microtubules Modification Molecular Mus Nature Non-Insulin-Dependent Diabetes Mellitus Organ Pathologic Pathway interactions Patients Pharmaceutical Preparations Physiological Play Process Protein Isoforms Recurrent disease Regulation Role Signal Transduction Source Stress Structure of beta Cell of islet Testing Therapeutic Time Tissues Transplantation Transportation Vacuole Work blood glucose regulation design diabetes pathogenesis diabetic feeding genetic approach in vivo innovation insight insulin secretion interdisciplinary approach interest islet live cell imaging mouse model novel novel therapeutics pathogen pharmacologic preservation prevent response superresolution imaging superresolution microscopy therapeutic target tool trafficking type I and type II diabetes

项目摘要

PROJECT SUMMARY Diabetes affects over 30 million Americans, yet its epidemic is still rising at an alarming rate. The progressive decline of pancreatic β cell function and mass is a hallmark of diabetes, but no medications prevent this decline. Interestingly, a fasting-mimicking diet known to activate autophagy stops this decline and reverses diabetes in mice. Accordingly, recent progress has increasingly recognized autophagy as a potential therapeutic target to treat diabetes because of its role in protecting β cells against pathogens and metabolic stress. However, the basic nature of β cell autophagy remains poorly understood, particularly in the molecular process governing autophagic membrane fission. Our recent data uncover that dynamin, a subfamily of large GTPases known to regulate endocytosis and insulin secretion, directly alters β cell autophagy. Live-cell imaging suggests that dynamin molecules can translocate to autolysosomes and drive autolysosome fission. Dynamin deletion causes striking autophagy defects in β cells in vitro and in vivo. These new findings fuel tremendous interest in understanding the molecule mechanisms at play throughout the β cell autophagy cycle. We hypothesize that dynamin plays a direct and crucial role in β cell autophagy flux that has not been characterized previously. Mechanistically, we suspect that dynamin regulates β cell autophagy through regulating autolysosome fission and autophagic transport. These processes may be essential to protect β cells against chronic metabolic stress toward diabetes. To test the hypothesis, we have generated dynamin isoform-specific mouse models, which allow evaluating dynamin-regulated β cell autophagy and its protection against metabolic stress associated with diabetes. We have assembled a team with substantial expertise in β cell biology, super-resolution imaging, biochemical signaling, and diabetes. We will focus on three specific aims. First, define the role of dynamin in β cell autolysosome fission. The fission step is necessary for autolysosome-to-lysosome transformation in each autophagic cycle of β cells, but its mechanism remains poorly understood. Second, identify the role of dynamin in regulating autophagic transport via microtubule modulation. This aim may uncover a previously unappreciated pathway for dynamin to regulate autophagy in β cells. Third, examine how dynamin regulates β cell autophagic responses upon metabolic stress in vivo. Together, these studies will provide new insights into the autophagic turnover in β cells and its regulation by different dynamin isoforms. The results will advance the fundamental understanding of β cell autophagy cycles that profoundly impacts islet function and diabetes pathogenesis.

项目摘要糖尿病会影响超过3000万美国人，但其流行病仍以惊人的速度上升。这胰腺β细胞功能和质量的逐渐下降是糖尿病的标志，但没有药物防止这种下降。有趣的是，已知会激活自噬的禁食饮食阻止了这一点衰落并逆转小鼠的糖尿病。根据某些确定，最近的进步已经得到了认识到自噬是治疗糖尿病的潜在治疗靶标，因为它在保护β细胞中的作用针对病原体和代谢胁迫。但是，β细胞自噬的基本性质仍然很差理解，尤其是在控制自噬膜裂变的分子过程中。我们的最新消息数据发现该动力蛋白是已知调节内吞作用和胰岛素的大型GTPases的亚科分泌，直接改变β细胞自噬。活细胞成像表明dynamin分子可以转移到自溶性并驱动自溶性裂变。 Dynamin删除导致罢工 β细胞体外和体内的自噬缺陷。这些新发现激发了人们对了解整个β细胞自噬周期中发挥作用的分子机制。我们假设Dynamin在尚未是β细胞自噬通量中起着直接而关键的作用以前是特征。从机械上讲，我们怀疑动力蛋白通过调节自溶性裂变和自噬运输。这些过程可能对保护至关重要 β细胞针对慢性代谢应激对糖尿病。为了检验假设，我们已经生成了 Dynamin同工型特异性小鼠模型，该模型允许评估动力蛋白调节的β细胞自噬并保护与糖尿病相关的代谢应激。我们已经组建了一个团队 β细胞生物学，超分辨率成像，生化信号传导和糖尿病方面的实质专业知识。我们将重点关注三个特定目标。首先，定义动力蛋白在β细胞自溶性裂变中的作用。裂变步骤对于每个自噬周期中的自溶剂体至液体体转化是必需的 β细胞，但其机制仍然很少理解。其次，确定Dynamin在通过微管调制调节自噬转运。这个目标可能会发现以前动力蛋白调节β细胞自噬的未批准途径。第三，检查如何动态在体内代谢应激时调节β细胞自噬反应。这些研究将在一起对β细胞中自噬的周转及其通过不同的动力蛋白的调节提供新的见解同工型。结果将提高对β细胞自噬周期的基本理解深刻影响胰岛功能和糖尿病发病机理。