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：
10016267
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：
2019
资助国家：
美国
起止时间：
2019-09-11 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016267
关键词：
4 year old Aging Anti-Inflammatory Agents Apoptosis Attenuated Beta Cell Blood Glucose CMV promoter CXCL10 gene Cell Survival Cell physiology Cell surface Cells Chemicals Cities Complex Data Defect Diabetes Mellitus Diabetes prevention Diet Disease Environment Exocytosis Failure Functional disorder Funding GLUT4 gene Genetic Transcription Glucose Intolerance Goals High Fat Diet Human Inflammatory Inflammatory Response Insulin Insulin Resistance Intervention Islet Cell Knockout Mice Link Longevity Membrane Metabolic dysfunction Mitochondria Molecular Morphology Mus Muscle function Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Obese Mice Outer Mitochondrial Membrane Patients Peripheral Population Prediabetes syndrome Predisposition Prevention Proteins RNA Regulation Research Role SNAP receptor Shock Signal Transduction Skeletal Muscle Stimulus Stress Structure of beta Cell of islet Suspensions Testing Therapeutic Tissues Translations Untranslated RNA Up-Regulation Vesicle Work base blood glucose regulation cell type cytokine diabetogenic glucose tolerance human tissue impaired glucose tolerance improved improved functioning in vivo inhibitor/antagonist innovation insight insulin secretion insulin sensitivity insulin sensitizing drugs islet mortality mouse model new therapeutic target novel novel therapeutics overexpression prevent protective effect stroke risk syntaxin 1 syntaxin 4 therapeutic candidate tool

项目摘要

Project Summary - Type 2 diabetes (T2D) plagues nearly 10% of the US population (~30 million people); a shocking 84 million more have prediabetes and show signs of impaired glucose tolerance. Compounding this problem, certain insulin-sensitizing drugs are undergoing global market suspensions, leaving prediabetic and T2D patients with few treatment options and creating an urgent need for new therapeutics. 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 (skm) insulin resistance are primary features of human prediabetes and T2D. STX4, a primary component of the SNARE exocytosis machinery, is reduced in β-cells and skm from humans with T2D. Furthermore, STX4 is required for normal β-cell insulin secretion and skm insulin sensitivity in mouse models and human islets. Our long-term goal is to understand how β-cell and skm signaling can be manipulated to prevent or reverse prediabetes and halt the progression to T2D. Our central hypothesis is that STX4 enrichment supports β-cells and/or skeletal muscle to prevent and reverse the damaging effects of diabetogenic stress. The rationale for the proposed research is that once these new mechanisms of STX4 are elucidated, STX4 signaling can be manipulated to prevent or reverse T2D. During the last funding cycle, we revealed new roles for STX4 in promoting β-cell survival and skm function. Indeed, mice overexpressing STX4 in these tissues have a remarkable 33% extended lifespan and are protected from aging- and diet-induced metabolic dysfunction. Also, we showed that STX4 can reverse insulin resistance in obese mice. However, the tissue-specific role of STX4 was unknown. Therefore, we generated inducible β-cell- and skm- specific STX4 overexpression and knockout mice, as well as RNA-based candidate therapeutics for tissue-specific STX4 enrichment. Our provocative new preliminary data indicate that STX4 participates in anti-inflammatory signaling in the β-cells, and localizes to the outer mitochondrial membrane to regulate mitochondrial function in skm. Therefore, the objective of this application is to test these candidate mechanisms linking STX4 enrichment and protection of β-cells and skm from diabetogenic stress and to evaluate candidate STX4 enrichment therapeutics. We will use our inducible mouse models and human tissues/cells for these studies. In Aim 1, we will evaluate the mechanisms underlying the protective actions of STX4 in β-cells and test novel β-cell STX4 enrichment strategies; in Aim 2, we will delineate how STX4 enrichment protects skm and how it reverses HFD-induced dysfunction. We will use innovative molecular tools to test novel hypotheses about STX4 action in the context of a translation-focused institutional environment at City of Hope. This work will positively impact diabetes research by evaluating a promising candidate strategy to reverse prediabetes and halt progression to T2D and by uncovering novel mechanisms of glycemic regulation.

项目摘要 - 2 型糖尿病 (T2D) 困扰着近 10% 的美国人口（约 3000 万人）；令人震惊的是，还有 8400 万人患有糖尿病前期并表现出糖耐量受损的迹象。问题，某些胰岛素增敏药物正在全球市场暂停，导致糖尿病前期和糖尿病患者 T2D 患者的治疗选择很少，因此迫切需要新的治疗方法。组织功能障碍导致糖尿病前期和进展为 T2D，预防或逆转这些疾病需要多管齐下，特别是胰腺 β 细胞功能障碍和骨骼肌 (skm) 胰岛素。耐药性是人类糖尿病前期和 T2D 的主要特征，STX4 是 SNARE 的主要组成部分。患有 T2D 的人的 β 细胞和 skm 中的胞吐机制减少，此外，STX4 也是其必需的。小鼠模型和人类胰岛的正常 β 细胞胰岛素分泌和 skm 胰岛素敏感性。目标是了解如何操纵 β 细胞和 skm 信号传导来预防或逆转糖尿病前期和我们的中心假设是 STX4 富集支持 β 细胞和/或骨骼。肌肉预防和逆转糖尿病应激的破坏性影响。研究表明，一旦阐明了 STX4 的这些新机制，就可以操纵 STX4 信号传导预防或逆转 T2D 在上一个融资周期中，我们揭示了 STX4 在促进 β 细胞方面的新作用。事实上，在这些组织中过度表达 STX4 的小鼠的存活率和 skm 功能显着提高了 33%。延长寿命并免受衰老和饮食引起的代谢功能障碍的影响。 STX4 可以逆转肥胖小鼠的胰岛素抵抗，但 STX4 的组织特异性作用尚不清楚。因此，我们还生成了可诱导的 β 细胞和 skm 特异性 STX4 过表达和敲除小鼠作为基于 RNA 的候选疗法，用于组织特异性 STX4 富集。数据表明，STX4 参与 β 细胞的抗炎信号传导，并定位于外层因此，本申请的目的是通过线粒体膜来调节 skm 中的线粒体功能。的目的是测试这些候选机制，将 STX4 富集与 β 细胞和 skm 的保护联系起来糖尿病应激并评估候选 STX4 富集疗法我们将使用我们的诱导小鼠。在目标 1 中，我们将评估这些研究的模型和人体组织/细胞。在目标 2 中，我们将研究 STX4 对 β 细胞的保护作用并测试新型 β 细胞 STX4 富集策略；描述 STX4 富集如何保护 skm 以及如何逆转 HFD 引起的功能障碍。创新的分子工具，用于在以翻译为中心的背景下测试有关 STX4 作用的新假设这项工作将通过评估希望之城的机构环境对糖尿病研究产生积极影响。逆转前驱糖尿病并阻止进展为 T2D 的有希望的候选策略，并通过发现新的血糖调节机制。