STARS-SRF Pathway- A Novel Regulator of Muscle Metabolism and Insulin Resistance

STARS-SRF 通路——肌肉代谢和胰岛素抵抗的新型调节剂

基本信息

批准号：
8495450
负责人：
Mary E Patti
金额：
$ 12.36万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-26 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495450
关键词：
5&apos -AMP-activated protein kinase Affect Americas Attention Cell Respiration Cell physiology Cells Data Defect Development Diabetes Mellitus Diabetes prevention Diet Energy Metabolism Epidemic Exercise Family Functional disorder Gene Expression Gene Expression Profile Gene Proteins Genes Genetic Genetic Risk Glucose Intolerance Human Individual Insulin Insulin Resistance Knock-out Knockout Mice Laboratories Link Longitudinal Studies Mediating Metabolic Metabolism Mitochondria Molecular Molecular Abnormality Mus Muscle Muscle Cells Muscle Fibers Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Patients Pattern Pharmacotherapy Play Population Prediabetes syndrome Predisposition Prevention Prevention approach Public Health Recording of previous events Resistance Risk Role Serum Response Factor Signal Transduction Skeletal Muscle Small Interfering RNA Striated Muscles Testing Transgenic Mice Transgenic Organisms United States adenylate kinase base diabetes risk disorder risk fatty acid oxidation genetic regulatory protein genome wide association study glucose metabolism glucose tolerance glucose transport high risk improved in vivo inhibitor/antagonist innovation insulin secretion insulin sensitivity insulin signaling mouse model muscle metabolism novel novel strategies novel therapeutic intervention overexpression rho small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) has reached epidemic proportions in the United States, affecting an estimated 8.3% of the population and inflicting enormous personal, public health, and financial tolls. Unfortunately, the cellular and molecular abnormalities that confer genetic and environmentally- determined diabetes risk remain incompletely understood. Thus, finding genes and pathways linked to T2D risk is essential for developing new and improved approaches to prevention and treatment. Recent studies from the Patti Lab have identified a novel, unexpected pattern of gene expression in skeletal muscle from human patients with established T2D. This pattern includes increased expression of genes regulated by serum response factor (SRF) and its upstream regulatory protein STARS (striated muscle activator of Rho-dependent signaling). Moreover, STARS expression correlates inversely with insulin resistance. Importantly, this pattern is also present in those at risk for disease based on family history, potentially linking this to risk for T2D (Jin and Patti, JCI 2011) Preliminary data indicate that the STARS-SRF pathway can robustly regulate muscle insulin resistance and systemic metabolism, contributing to T2D pathophysiology. Specifically, activation of STARS-SRF induces insulin resistance and reduces fatty acid oxidation, while inhibition of SRF or reduced STARS expression improves mitochondrial oxidative metabolism and increases insulin- stimulated glucose transport in myotubes. Moreover, STARS-null mice are resistant to diet-induced obesity and glucose intolerance, potentially via increased exercise capacity and energy expenditure. This proposal focuses on testing the innovative hypothesis that activation of STARS-SRF plays a pivotal role in promoting insulin resistance, and that inhibition of this pathway is a novel therapeutic approach for T2D. Three specific aims are proposed to test these hypotheses and to elucidate molecular mechanisms mediating these effects: (1) To determine the metabolic consequences of STARS-SRF activation, by assessing insulin action, glucose transport, and oxidative metabolism in myotubes overexpressing STARS and in muscle-specific STARS transgenic mice. (2) To identify mechanisms by which STARS-SRF modulates oxidative metabolism and insulin sensitivity by detailed analysis of mitochondrial mass/function & insulin signaling in primary myotubes from both STARS-null and STARS-transgenic mice. Since preliminary data indicate that STARS-SRF inhibition activates AMP kinase, we will test whether STARS effects on oxidative metabolism are mediated via AMP kinase. (3) To utilize specific SRF inhibitors to dissect pathways mediating improved insulin action and oxidative metabolism in cultured myotubes, and determine whether these inhibitors can similarly improve glucose metabolism and energy expenditure in vivo, in mice with obesity and T2D.

描述（由申请人提供）：2型糖尿病（T2D）在美国达到了流行比例，影响了估计的8.3％的人口，并造成了巨大的个人，公共卫生和财务收费。不幸的是，赋予遗传和环境确定的糖尿病风险的细胞和分子异常尚不完全了解。因此，寻找与T2D风险相关的基因和途径对于开发新的和改进的预防和治疗方法至关重要。 Patti Lab的最新研究确定了来自已建立T2D的人类患者骨骼肌中新型基因表达的新颖，意外的模式。该模式包括增加由血清反应因子（SRF）调节的基因表达及其上游调节蛋白星（Rho依赖性信号的横纹肌肉激活因子）。此外，恒星表达与胰岛素抵抗成反比。重要的是，这种模式在基于家族史的疾病风险中也存在，可能将其与T2D的风险联系起来（Jin和Patti，JCI，JCI 2011），这表明Stars-SRF途径可以牢固地调节肌肉胰岛素抵抗和全身性。代谢，促进T2D病理生理学。具体而言，恒星-SRF的激活诱导胰岛素抵抗并降低脂肪酸氧化，而抑制SRF或减少恒星表达可改善线粒体氧化代谢，并增加肌动物中胰岛素刺激的葡萄糖转运。此外，恒星无小鼠对饮食诱导的肥胖症和葡萄糖不耐症具有抵抗力，这可能会通过增加运动能力和能量消耗。该提案的重点是检验创新的假设，即星-SRF的激活在促进胰岛素抵抗中起关键作用，而抑制这种途径是T2D的一种新型治疗方法。提出了三个特定的目的来检验这些假设并阐明介导这些作用的分子机制：（1）通过评估胰岛素作用，葡萄糖传输和在肌肉过表达的恒星以及肌肉过表达的恒星，以及肌肉过表达的肌肉和肌肉中的氧化代谢，以确定星-SRF激活的代谢后果。 - 特异性恒星转基因小鼠。（2）通过详细分析恒星 - 孔和恒星 - 转基因小鼠的原代肌管中的线粒体质量/功能/功能和胰岛素信号传导的详细分析，通过详细分析了恒星-SRF来调节氧化代谢和胰岛素敏感性的机制。由于初步数据表明恒星-SRF抑制会激活AMP激酶，因此我们将测试恒星对氧化代谢是否通过AMP激酶介导的影响。（3）利用特定的SRF抑制剂来剖析培养的肌管中介导的胰岛素作用和氧化代谢的介导的途径，并确定这些抑制剂在肥胖症和T2D中是否可以类似地改善小鼠的体内葡萄糖代谢和能量支出。