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Regulating SNARE mechanisms to remediate glucose homeostasis

调节 SNARE 机制修复葡萄糖稳态

基本信息

批准号：
8759392
负责人：
Debbie C Thurmond
金额：
$ 33.62万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-07 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8759392
关键词：
Adipose tissue Age Attenuated Beta Cell Binding Biochemical Biological Assay Biosensor Blood Glucose Cell membrane Cell physiology Cells Coin Complex Data Defect Development Diabetes Mellitus Diabetic mouse Diagnosis Diet Disease Docking Epidemic Event Exhibits Exocytosis Exposure to Failure Fatty acid glycerol esters Functional disorder Funding GLUT4 gene Genetic Glucose Goals Health Human Hyperglycemia Impairment Incidence Inflammation Insulin Insulin Resistance Intake Intervention Islet Cell Islets of Langerhans Knockout Mice Lead Life Link Longevity Messenger RNA Molecular Mus Muscle Cells Muscle Fibers Myocardial Infarction Names Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Pancreas Peptides Peripheral Plague Population Prediabetes syndrome Predisposition Prevention Process Proteins Regulation Research Rodent SNAP receptor Shock Skeletal Muscle Solutions Stimulus Stress Stroke Testing Tissues Transgenic Mice Up-Regulation Vesicle Work base blood glucose regulation cellular imaging diabetic feeding functional restoration glucose tolerance glucose uptake glycemic control human tissue impaired glucose tolerance improved in vivo innovation insulin secretion insulin sensitivity islet mortality new therapeutic target novel receptor regenerative restoration soluble NSF attachment protein syntaxin 4 target SNARE proteins

项目摘要

DESCRIPTION (provided by applicant): Incidences of type 2 diabetes (T2D) have reached epidemic proportions, with ~8.3% of the US population diagnosed and 79 million more exhibiting pre-diabetes - a reminder of the urgent need for solutions. Halting pre-diabetes development and progression to T2D requires a multi-pronged approach, since the pathophysiology involves both peripheral insulin resistance and pancreatic β cell dysfunction. Each of these processes is rate-limited by the abundance of exocytosis t-SNARE (Soluble NSF Attachment Protein Receptor) proteins. Relatedly, a recent human islet study suggests that increasing expression of exocytosis proteins, such as the t-SNARE protein Syntaxin 4 (Syn4), may lead to improved regenerative approaches to treat diabetes. Loss of Syn4 abundance and/or its activity is associated with diabetes in human and rodent islets and skeletal muscle, tissues which regulate insulin release and insulin sensitivity, respectively. Thus, the long-term goal is to understand how Syn4 can be manipulated for treatment and prevention of prediabetes and T2D. Discovery of ways to target Syn4 abundance/activation to control glycemic dysregulation and prediabetes offers a tantalizing opportunity for disease intervention. The objective of this application is to determine how Syn4 enrichment/activation functions to enhance β-cell insulin secretion and skeletal muscle insulin action both in vivo and at the molecular level, and how Syn4 abundance in these tissues is regulated. Preliminary data show that Syn4 protein is limiting for human islet insulin secretion; islets enriched with Syn4 more effectively reduce hyperglycemia in diabetic mice. Moreover, T2D human islets are ~40% deficient in Syn4 protein, as are islet and muscle cells of diabetic mice. Notably, restoration of Syn4 to human T2D islets can fully rescue insulin secretion. Syn4-enriched mice also resist age-and high-fat-diet induced insulin resistance. The central hypothesis is that diabetogenic stimuli underlie Syn4 deficiency to impair key regulated exocytosis events in β cells and skeletal muscle cells, and that Syn4 upregulation can boost these processes to rescue/resist stress associated with prediabetes and T2D. The rationale for the proposed research is that once it is known how Syn4 enrichment promotes and/or protects functional β cell mass and peripheral insulin sensitivity, and how Syn4 abundance is regulated, that Syn4 can be manipulated to avert disease in the face of diabetogenic stimuli. Three Specific Aims are developed to test this: 1) Evaluate Syn4 upregulation in prevention/reversal of diabetogenic-induced β-cell dysfunction, 2) Delineate how Syn4 enrichment/activation in skeletal muscle promotes insulin sensitivity, and 3) Determine the mechanistic basis for attenuated Syn4 expression in pre/diabetic tissues. Aims will be accomplished using innovative inducible β-cell- and skeletal muscle-specific Syn4 transgenic mice challenged with diabetogenic stimuli, peptide activators of endogenous Syn4, and live-cell imaging biosensors paired with biochemical assays using human tissues. Results will positively impact efforts to ameliorate disease as the identified mechanisms are highly likely to provide new therapeutic targets.

描述（由申请人提供）：2 型糖尿病 (T2D) 的发病率已达到流行病的程度，约 8.3% 的美国人口被诊断出患有糖尿病前期，另有 7,900 万人患有糖尿病前期，这提醒人们迫切需要解决方案。阻止糖尿病前期发展和进展为 T2D 需要多管齐下，因为病理生理学涉及外周胰岛素抵抗和胰腺 β 细胞功能障碍。这些过程中的每一个都受到胞吐作用 t-SNARE（可溶性 NSF 附着蛋白受体）蛋白丰度的速率限制。与此相关的是，最近的一项人类胰岛研究表明，增加胞吐蛋白（例如 t-SNARE 蛋白 Syntaxin 4 (Syn4)）的表达，可能会改善治疗糖尿病的再生方法。 Syn4 丰度和/或其活性的丧失与人类和啮齿动物胰岛和骨骼肌（分别调节胰岛素释放和胰岛素敏感性的组织）中的糖尿病有关。因此，长期目标是了解如何操纵 Syn4 来治疗和预防糖尿病前期和 T2D。发现以 Syn4 丰度/激活为目标来控制血糖失调和糖尿病前期的方法为疾病干预提供了诱人的机会。本应用的目的是确定 Syn4 富集/激活如何在体内和分子水平上增强 β 细胞胰岛素分泌和骨骼肌胰岛素作用，以及如何调节这些组织中的 Syn4 丰度。初步数据表明，Syn4蛋白限制人胰岛胰岛素分泌；富含 Syn4 的胰岛可以更有效地降低糖尿病小鼠的高血糖。此外，T2D 人类胰岛约 40% 缺乏 Syn4 蛋白，糖尿病小鼠的胰岛和肌肉细胞也是如此。值得注意的是，将 Syn4 恢复到人类 T2D 胰岛中可以完全恢复胰岛素分泌。富含 Syn4 的小鼠还可以抵抗年龄和高脂肪饮食引起的胰岛素抵抗。核心假设是，导致糖尿病的刺激是 Syn4 缺陷的基础，会损害 β 细胞和骨骼肌细胞中关键的调节胞吐作用事件，而 Syn4 上调可以促进这些过程，以挽救/抵抗与前驱糖尿病和 T2D 相关的压力。这项研究的基本原理是，一旦了解 Syn4 富集如何促进和/或保护功能性 β 细胞质量和外周胰岛素敏感性，以及如何调节 Syn4 丰度，就可以在面对糖尿病刺激时操纵 Syn4 来避免疾病。开发了三个具体目标来测试这一点：1) 评估 Syn4 上调在预防/逆转糖尿病引起的 β 细胞功能障碍中的作用，2) 描述骨骼肌中 Syn4 的富集/激活如何促进胰岛素敏感性，以及 3) 确定糖尿病前期/糖尿病组织中 Syn4 表达减弱的机制基础。目标将通过使用创新的诱导型 β 细胞和骨骼肌特异性 Syn4 转基因小鼠来实现，该小鼠接受糖尿病刺激、内源性 Syn4 肽激活剂和活细胞成像生物传感器，并结合使用人体组织的生化测定。结果将对改善疾病的努力产生积极影响，因为已确定的机制很可能提供新的治疗靶点。