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）几乎吞噬了美国人口的10％（约3000万人）；一个令人震惊的8400万具有糖尿病前期，并显示出葡萄糖耐受性受损的迹象。使这个更加复杂问题，某些胰岛素敏感药物正在经历全球市场悬架，留下糖尿病前期和 T2D患者几乎没有治疗选择，并且迫切需要新治疗。因为多组织功能障碍有助于糖尿病前期和进展为T2D，预防或反向这些疾病需要一种多管齐的方法。具体而言，胰腺β细胞功能障碍和骨骼肌（SKM）胰岛素抗性是人类前观和T2D的主要特征。 STX4，SNARE的主要组成部分胞吐作用机制在具有T2D的人类的β细胞和SKM中降低。此外，STX4是必需的小鼠模型和人类胰岛中正常的β细胞胰岛素分泌和SKM胰岛素敏感性。我们的长期目标是了解如何操纵β细胞和SKM信号传导以防止或反向前糖尿病以及停止进展到T2D。我们的中心假设是STX4富集支持β细胞和/或骨骼肌肉预防和扭转糖尿病胁迫的破坏作用。提议的理由研究是，一旦阐明了这些新机制，可以将STX4信号操纵为预防或反向T2D。在上一个融资周期中，我们揭示了STX4在促进β细胞中的新作用生存和SKM功能。实际上，在这些时代过表达STX4的小鼠具有惊人的33％延长寿命，并受到衰老和饮食诱导的代谢功能障碍的保护。另外，我们表明 STX4可以逆转肥胖小鼠的胰岛素抵抗。但是，STX4的组织特异性作用尚不清楚。因此，我们还产生了诱导的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。我们挑衅的新初步数据表明STX4参与β细胞中的抗炎信号传导，并定位于外部线粒体膜调节SKM中的线粒体功能。因此，此应用程序的目的是测试这些候选机制，这些机制将stx4富集和保护β细胞和SKM连接起来糖尿病性应激并评估候选STX4富集疗法。我们将使用诱导的鼠标这些研究的模型和人体组织/细胞。在AIM 1中，我们将评估该机制 STX4在β细胞和测试新型β细胞STX4富集策略中的保护作用；在AIM 2中，我们将描述STX4富集如何保护SKM及其如何逆转HFD诱导的功能障碍。我们将使用在以翻译为中心的背景下，用于测试有关STX4动作的新假设的创新分子工具希望之城的机构环境。这项工作将通过评估A来积极影响糖尿病研究有希望的候选策略将糖尿病前期和停止向T2D的进展以及通过揭示新颖的策略血糖调节的机制。