权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10677652
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/10677652
关键词：
4 year old Aging Anti-Inflammatory Agents Apoptosis Beta Cell Blood Glucose CMV promoter CXCL10 gene Cell Survival Cell physiology Cell surface Cells Chemicals Cities Complex Data Defect Diabetes Mellitus Diet Disease Environment Exocytosis Failure Functional disorder Funding GLUT 4 protein Genetic Transcription Glucose Goals High Fat Diet Human Inflammatory Inflammatory Response Institution Insulin Insulin Resistance Intervention Islet Cell Knockout Mice Link Longevity Marketing Membrane Metabolic dysfunction Mitochondria Molecular Morphology Mus Muscle function Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Obese Mice Outer Mitochondrial Membrane Patients Peripheral Persons Population Prediabetes syndrome Predisposition Prevention Proteins RNA Regulation Research Role SNAP receptor Signal Transduction Skeletal Muscle Stimulus Stress Structure of beta Cell of islet Suspensions Testing Therapeutic Tissues Translations Untranslated RNA Up-Regulation Vesicle Work blood glucose regulation cell type cytokine diabetogenic functional improvement glucose tolerance human tissue impaired glucose tolerance improved in vivo inhibitor innovation insight insulin secretion insulin sensitivity insulin sensitizing drugs islet mortality mouse model new therapeutic target novel novel therapeutics overexpression posttranscriptional prevent protective effect remediation 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)；a 令人震惊的是，还有8400万人患有糖尿病前期，并显示出糖耐量受损的迹象。使这一点复杂化问题是，某些胰岛素敏感型药物正在全球市场暂停销售，导致糖尿病前期和 T2D患者几乎没有治疗选择，迫切需要新的治疗方法。因为多个- 组织功能障碍有助于糖尿病前期和发展为T2D，预防或逆转这些疾病需要多管齐下。具体地说，胰腺β细胞功能障碍和骨骼肌胰岛素抵抗是人类糖尿病前期和T2D的主要特征。STX4，圈套的主要组成部分胞吐机制，减少了β-细胞和来自人类的干细胞。此外，还需要使用STX4 小鼠模型和人胰岛的正常β细胞胰岛素分泌和SKM胰岛素敏感性。我们的长期合作目标是了解β-细胞和SKM信号如何被操纵来预防或逆转糖尿病前期和停止向T2D的进展。我们的中心假设是，STX4的浓缩支持β细胞和/或骨骼预防和逆转糖尿病应激对肌肉的损害作用。建议的理由是研究表明，一旦STX4的这些新机制被阐明，STX4信号就可以被操纵来防止或反转T2D。在上一个资助周期中，我们揭示了stx4在促进β-cell方面的新角色。生存与SKM功能。事实上，在这些组织中过度表达STX4的小鼠有显著的33% 延长寿命，防止衰老和饮食引起的代谢功能障碍。此外，我们还展示了 STX4可以逆转肥胖小鼠的胰岛素抵抗。然而，STX4的组织特异性作用尚不清楚。因此，我们还产生了可诱导的β细胞和SKM特异性的stx4过表达和基因敲除小鼠作为组织特异性STX4浓缩的基于RNA的候选疗法。我们挑衅性的新预赛研究表明，stx4参与了β细胞的抗炎信号转导，并定位于细胞外线粒体膜调节SKM的线粒体功能。因此，此应用程序的目标是是为了测试这些候选机制，这些机制将stx4浓缩和保护β-细胞和SKM 糖尿病应激和评估STX4强化治疗的候选药物。我们将使用我们诱导的小鼠用于这些研究的模型和人体组织/细胞。在目标1中，我们将评估 STX4在β细胞中的保护作用和测试新的β细胞STX4浓缩策略；在目标2中，我们将描述STX4的增加如何保护SKM以及它如何逆转HFD诱导的功能障碍。我们将使用创新的分子工具在以翻译为重点的背景下测试关于STX4作用的新假说希望之城的制度环境。这项工作将对糖尿病研究产生积极影响有望逆转糖尿病前期和阻止进展为T2D的候选策略以及通过发现新的血糖调节机制。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Munc18c depletion selectively impairs the sustained phase of insulin release.

MUNC18C耗竭选择性损害胰岛素释放的持续相。

DOI：
10.2337/db08-1059
发表时间：
2009-05
期刊：
Diabetes
影响因子：
7.7
作者：
Oh E;Thurmond DC
通讯作者：
Thurmond DC

Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis.

DOI：
10.1083/jcb.201007176
发表时间：
2011-04-04
期刊：
The Journal of cell biology
影响因子：
0
作者：
Jewell JL;Oh E;Ramalingam L;Kalwat MA;Tagliabracci VS;Tackett L;Elmendorf JS;Thurmond DC
通讯作者：
Thurmond DC

Novel roles for insulin receptor (IR) in adipocytes and skeletal muscle cells via new and unexpected substrates.

胰岛素受体（IR）在脂肪细胞和骨骼肌细胞中通过新的和意外的底物中的新作用。