DOC2B-based therapeutics for prevention/remediation of type 2 diabetes

基于 DOC2B 的 2 型糖尿病预防/治疗疗法

基本信息

批准号：
10165703
负责人：
Debbie C Thurmond
金额：
$ 43.25万
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：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165703
关键词：
Apoptosis Beta Cell Binding Biochemical Biological Assay Biosensor Blood Glucose CXCL9 gene Cell membrane Cells Complex Data Defect Development Diabetes prevention Disease Docking Exocytosis Functional disorder GLUT 4 protein Genes Glucose Intolerance Goals Health Heat-Shock Proteins 70 High Fat Diet Human Inflammation Insulin Insulin Resistance Intervention Islet Cell Laboratories Methods Microtubules Molecular Motor Mus Muscle Cells Muscle Fibers Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Outcome Pancreas Patients Peptide Fragments Peptides Peripheral Phosphorylation Population Prediabetes syndrome Predisposition Prevention Process Proteins RNA Research Rodent Role SNAP receptor Shock Skeletal Muscle Stimulus Streptozocin Stress Structure of beta Cell of islet Suspensions Testing Therapeutic Tissues Transgenic Mice Up-Regulation Vesicle Work base blood glucose regulation cell type cytokine design diabetogenic glucose tolerance glucose uptake glycemic control human tissue impaired glucose tolerance improved improved functioning in vivo innovation insulin secretion insulin sensitivity insulin sensitizing drugs islet live cell imaging mortality novel therapeutic intervention overexpression prevent remediation response skeletal muscle wasting stroke risk translational approach

项目摘要

Type 2 diabetes (T2D) plagues nearly 10% of the US population; a shocking 86 million more have prediabetes, and show signs of impaired glucose tolerance. Compounding this problem, certain insulin-sensitizing drugs are undergoing global market suspensions due to severe health complications, leaving prediabetic and T2D patients with fewer treatment options. Because multi-tissue dysfunction contributes to prediabetes and progression to T2D, prevention or reversal of these diseases requires a multi-pronged approach. Specifically, pancreatic β-cell dysfunction and skeletal muscle insulin resistance are primary features of human prediabetes and T2D. DOC2B, a key regulator of exocytosis proteins, is required for normal insulin secretion (from islet β-cells) and peripheral insulin sensitivity for normal glucose uptake (in skeletal muscle); loss of DOC2B abundance is associated with prediabetes and T2D in human and rodent islets and skeletal muscle, and DOC2B+/- mice are more susceptible to impaired glucose tolerance. Thus, the long-term goal is to understand how vesicle exocytosis mechanisms can be manipulated to prevent and/or reverse prediabetes and halt the progression to T2D. Recent discoveries of new functions of DOC2B in exocytosis, plus new methods to target DOC2B abundance and/or capitalize on its tissue-specific functions to control glycemic dysregulation, offer an enticing and untapped opportunity for disease intervention. The objective of this application is to determine how DOC2B enrichment enhances β-cell insulin secretion and skeletal muscle insulin sensitivity in human tissues, in vivo, and at the molecular level. Preliminary data show that DOC2B upregulation in β-cells increases the function of human T2D islets, diminishes cytokine-induced apoptosis, and protects mice from diabetogenic stimuli. Moreover, DOC2B functions in skeletal muscle to increase vital complex formation amongst exocytosis proteins, and a peptide fragment of DOC2B can recapitulate this function. The central hypothesis is that DOC2B is essential for insulin release and glucose uptake in β-cells and skeletal muscle, respectively, and that DOC2B upregulation can improve insulin/glucose regulation to prevent or reverse prediabetes. The rationale for the proposed research is that once it is known how DOC2B enrichment protects glucose homeostasis, DOC2B can be manipulated to prevent or reverse prediabetes. Two Specific Aims are designed to test this: 1) Evaluate DOC2B enrichment in the prevention/reversal of diabetogenic stimuli-induced β-cell dysfunction and demise, and 2) Delineate how DOC2B enrichment in skeletal muscle promotes insulin sensitivity. We will use innovative inducible β-cell- and skeletal muscle-specific DOC2B transgenic mice for mechanistic discovery. We will also test translational approaches for increasing DOC2B expression and function, using live-cell imaging biosensors paired with biochemical assays in human cells/tissues. The results will positively impact efforts to ameliorate prediabetes as the identified mechanisms are highly likely to provide new therapeutic strategies.

2型糖尿病（T2D）瘟疫几乎占美国人口的10％；令人震惊的8600万具有糖尿病前期，并显示出葡萄糖耐受性受损的迹象。由于严重的健康并发症，使某些胰岛素敏化药物的问题更加复杂，某些胰岛素敏化药物正在经历全球市场悬架，使糖尿病前和T2D患者的治疗选择较少。由于多组织功能障碍有助于糖尿病前期，并进展为T2D，因此这些疾病的预防或逆转需要多管齐全的方法。具体而言，胰腺β细胞功能障碍和骨骼肌胰岛素抵抗是人类前和T2D的主要特征。 DOC2B是胞吐蛋白的关键调节剂，是正常胰岛素分泌（来自胰岛β细胞）和外周胰岛素敏感性（在骨骼肌中）所必需的； DOC2B丰度的丧失与人类和啮齿动物胰岛和骨骼肌的T2D有关，而DOC2B +/-小鼠更容易受到葡萄糖耐受性的影响。这就是长期目标是了解如何操纵囊泡胞吐机制，以预防和/或反向预测并停止发展为T2D。 DOC2B新功能在胞吞作用中的最新发现，以及针对DOC2B抽象和/或利用其组织特异性功能的新方法，以控制血糖失调，为疾病干预提供了诱人的和未开发的机会。该应用的目的是确定doc2b如何增强人体组织，体内和分子水平的β细胞胰岛素分泌和骨骼肌胰岛素敏感性。初步数据表明，β细胞的进展增加了人类T2D小岛的功能，减少了细胞因子诱导的细胞凋亡，并保护小鼠免受糖尿病性刺激。此外，DOC2B在骨骼肌中的功能增加了胞吐蛋白之间的重要复合形成，并且DOC2B的肽片段可以概括此功能。中心假设是DOC2B分别对于β细胞和骨骼肌的胰岛素释放和葡萄糖摄取至关重要，并且DOC2B上调可以改善胰岛素/葡萄糖调节以预防或逆转糖尿病。拟议的研究的理由是，一旦知道了doc2b富集如何保护葡萄糖稳态，则可以操纵DOC2B来预防或逆转糖尿病。设计了两个具体目的来测试以下方面：1）评估doc2b富集的预防/逆转糖尿病性刺激诱导的β细胞功能障碍和衰减，以及2）2）描述骨骼肌中doc2b富集如何促进胰岛素敏感性。我们将使用创新的诱导型β细胞和骨骼肌特异性DOC2B转基因小鼠进行机械发现。我们还将使用与人类细胞/组织中的生化测定配对的活细胞成像BIOSENORS测试翻译方法，以增加DOC2B的表达和功能。由于确定的机制极有可能提供新的治疗策略，因此结果将积极影响减轻糖尿病前期的努力。