Novel mechanistic pathways of cardiovascular disease in obesity

肥胖症心血管疾病的新机制途径

基本信息

批准号：
8911095
负责人：
David J Fulton
金额：
$ 55.54万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8911095
关键词：
Age Animals Binding Biology Blood Pressure Blood Vessels Body Weight decreased Carbohydrates Cardiac Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Clinic Clinical Data Defect Diabetes Mellitus Endothelium Exercise Experimental Models Extracellular Space Family member Functional disorder Galactosides Galectin 3 Gene Deletion Gene Expression Genes Genetic Glucose Goals Growth Health Human In Vitro Injury Insulin Resistance Intervention Intracellular Space Lectin Light Link Lipids Measures Mediating Mediator of activation protein Metabolic Metabolic Control Metabolic Diseases Metabolism Methods Molecular Morbidity - disease rate Mus Muscle Mutation NADPH Oxidase 1 Obese Mice Obesity Outcome Oxidants Pathway interactions Patients Performance Pharmaceutical Preparations Physiological Physiology Plasma Population Production Proteins Reactive Oxygen Species Regulation Research Risk Factors Role Secondary to Signal Transduction Skeletal Muscle Stimulus Stress Superoxides Techniques Testing Translations Up-Regulation Vascular Diseases Vasodilation Weight base cardiovascular health cardiovascular injury db/db mouse glucose disposal glucose tolerance hemodynamics improved in vivo insulin signaling mortality muscle form myostatin new therapeutic target novel overexpression oxidant stress public health relevance research study response targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Morbidity and mortality secondary to cardiovascular disease is the major health problem in obese patients. Obese patients are burdened with an array of metabolic dysfunctions associated with excess weight which drive the cardiovascular disease evident in this population. While this correlation is well-established, mechanistic links that could be exploited therapeutically are largely lacking. In preliminary studies for this proposal, we have made two major observations that shed significant new light on this issue. The first is that loss of metabolic control in skeletal muscle appears to be the key trigger for vascular injury in obesity. Correction of rapid glucose disposal by deletion of genes that limit insulin signaling or muscle growth appear to restore endothelial function in vitro and may underpin cardiovascular defects systemically. The second observation is the NADPH Oxidase 1 (Nox1) is a major culprit in vascular defects in obesity. Nox1 is overexpressed in large and small vessels from obese mice and appears driven by glucose excess, potentially via upregulation of galectin-3. In the current proposal, we will rigorously test these concepts in three aims. The firs aim will use state-of-the-art molecular techniques in vitro to determine the signaling mechanisms by which changes in the plasma milieu, specifically glucose, induce changes in Nox expression and superoxide production with specific emphasis on the role of galectin-3. The second aim will generate novel Nox1 and Galectin-3 KO mice on a genetically obese background to test the hypothesis that these two oxidant pathways contribute to vascular dysfunction in vitro with a specific emphasis on determining whether improving metabolism by increasing muscle mass obviates pro oxidant pathways. The third aim will pursue these concepts in vivo, testing whether increased muscle mass or blocking the Nox1/Galectin-3 signaling axis improves cardiovascular outcomes like blood pressure and vascular adaptions to hemodynamic stress. Taken together, these studies will provide new information on the mechanisms, mediators and physiologic impact of obesity-induced metabolic dysfunction. Successful completion of these aims may identify new targets to aid in the treatment of some the most pressing clinical outcomes of obesity.

描述（由申请人提供）：继发于心血管疾病的发病率和死亡率是肥胖患者的主要健康问题，肥胖患者患有一系列与体重过重相关的代谢功能障碍，而这种相关性在该人群中很明显。虽然这一点已得到证实，但在该提议的初步研究中，很大程度上缺乏可用于治疗的机制联系，我们做出了两项重要的观察，为这一问题提供了重要的新线索：第一个是骨骼代谢控制的丧失。肌肉似乎是肥胖症中血管损伤的关键触发因素，通过删除限制胰岛素信号或肌肉生长的基因来纠正快速葡萄糖处理似乎可以在体外恢复内皮功能，并可能增强全身性心血管缺陷。 Nox1 (Nox1) 是肥胖小鼠血管缺陷的罪魁祸首，目前，Nox1 在肥胖小鼠的大血管和小血管中过度表达，可能是由葡萄糖过量驱动的，可能是通过上调半乳糖凝集素 3 来实现的。根据提议，我们将在三个目标中严格测试这些概念，第一个目标将使用最先进的体外分子技术来确定血浆环境（特别是葡萄糖）的变化诱导 Nox 表达和变化的信号传导机制。第二个目标是在遗传性肥胖背景下产生新型 Nox1 和 Galectin-3 KO 小鼠，以测试这两种氧化途径在体外以特定的方式导致血管功能障碍的假设。重点是确定是否通过增加肌肉质量来改善新陈代谢，从而消除促氧化途径。第三个目标是在体内研究这些概念，测试增加肌肉质量或阻断 Nox1/Galectin-3 信号轴是否可以改善心血管结果，例如血压和血管适应。总而言之，这些研究将提供有关肥胖引起的代谢功能障碍的机制、介质和生理影响的新信息，这些目标的成功完成可能会成为确定治疗某些最紧迫的临床结果的新目标。肥胖。