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：
9069140
负责人：
Debbie C Thurmond
金额：
$ 36.98万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069140
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（通过应用程序提供）：2型糖尿病（T2D）的事件已达到流行比例，约8.3％的美国人口诊断，还有7900万人出现了糖尿病前期的糖尿病 - 提醒人们迫切需要解决方案。停止糖尿病前的发育和进展为T2D需要多管齐下的方法，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是由胞吐作用T-SNARE（可溶性NSF附着蛋白受体）蛋白的抽象限制的。相关的是，最近的人类胰岛研究表明，增加胞吐蛋白的表达增加，例如T-SNARE蛋白语法4（SYN4），可能会改善治疗糖尿病的再生方法。 Syn4抽象和/或其活性的丧失与人类和啮齿动物胰岛中的糖尿病以及骨骼肌，分别调节胰岛素释放和胰岛素敏感性的组织有关。这是长期目标是了解如何操纵Syn4以治疗和预防糖尿病前期和T2D。发现靶向Syn4抽象/激活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。该应用的目的是确定Syn4增强/激活功能如何增强体内和分子水平的β细胞胰岛素分泌和骨骼肌胰岛素作用，以及如何调节这些尖端中的Syn4抽象。初步数据表明，Syn4蛋白是人类胰岛胰岛素分泌的限制。富含Syn4的胰岛更有效地减少了糖尿病小鼠的高血糖。此外，T2D人类胰岛以及糖尿病小鼠的胰岛和肌肉细胞的缺陷约40％。值得注意的是，将Syn4恢复为人类T2D小岛可以完全挽救胰岛素的分泌。富含Syn4的小鼠还可以抵抗年龄和高脂诱导的胰岛素耐药性。中心假设是糖尿病生成刺激是同步缺乏症的基础，以损害β细胞和骨骼肌细胞中关键调节的胞吐事件，并且同步可以提高这些过程以挽救与糖尿病前期和T2D相关的应激。拟议的研究的基本原理是，一旦知道了Syn4富集如何促进和/或保护功能性β细胞量和外周胰岛素敏感性，以及如何调节Syn4抽象，则可以在糖尿病发作刺激面前操纵Syn4。开发了三个特定目的来测试以下三个特定目标：1）评估糖尿病诱导的β细胞功能障碍的预防/反转中的同步上调，2）描绘骨骼肌中的Syn4富集/激活如何促进胰岛素敏感性，3）确定actenten的Syn4表达在预/糖尿病组织中的机械基础。将使用创新的诱导型β细胞和骨骼肌特异性同步小鼠来实现目标，这些小鼠面临着糖尿病刺激，内源性Syn4的胡椒激活剂以及使用人体组织与生物化学分析配对的活细胞成像生物传感器。结果将对改善疾病的努力产生积极影响，因为确定的机制很可能提供新的治疗靶标。