The role of GLP-1 in cardiac recovery after bariatric surgery in obesity-induced heart failure

GLP-1 在肥胖引起的心力衰竭减肥手术后心脏恢复中的作用

基本信息

批准号：
10320340
负责人：
Tammy Lyn Kindel
金额：
$ 15.09万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
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：
2019-01-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320340
关键词：
Advisory Committees Agonist Apoptosis Award Biochemical Biochemistry Biology Body Weight decreased Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Clinical Clinical Sciences Development Disease Engineering Environment Extramural Activities Fibrosis Functional disorder Funding GLP-I receptor Gastrectomy Gastrointestinal Hormones Goals Heart Diseases Heart failure Human In Vitro Institutes Intervention Investigation K-Series Research Career Programs Lead Mediating Mentors Mentorship Messenger RNA Metabolic Metabolic stress Modeling Molecular Morbid Obesity Muscle Cells Myocardial dysfunction Myocardium Nuclear Receptors Obesity Operative Surgical Procedures PPAR alpha Pathogenesis Pathway interactions Physiological Pluripotent Stem Cells Rattus Receptor Activation Receptor Signaling Recovery Recovery of Function Regulation Research Research Personnel Resources Risk Role SLC2A1 gene Serum Signal Pathway Signal Transduction Stress Structure Techniques Testing Training Training Programs Transgenic Organisms Translating Translational Research United States National Institutes of Health Wisconsin antagonist bariatric surgery cell injury collaborative environment dieting fatty acid oxidation glucagon-like peptide 1 heart disease risk heart function hemodynamics improved in vivo insulin signaling medical schools novel obese patients obese person obesity treatment oxidation skills stem cell technology

项目摘要

Project Summary Obesity cardiomyopathy is an increasingly prevalent and morbid disease of myocyte dysfunction causing heart failure due to severe obesity. Even though weight reduction through dieting fails to improve cardiac function, obesity treatment with bariatric surgery, like a sleeve gastrectomy (SG), significantly improves cardiac function. The inciting mechanisms for cardiac recovery after SG are poorly understood. This project will explore the novel hypothesis that cardiac glucagon-like peptide-1 receptor (GLP-1R) signaling results in the activation of the nuclear receptor peroxisome proliferator activated receptor alpha (PPARα), resulting in improved cardiac function. The applicant has found that a SG performed in obese rats significantly improved cardiac function, independent of weight loss, associated with increased serum GLP-1, increased cardiac PPARα, and decreased cardiac apoptosis, fibrosis and changes in substrate utilization. The specific aims of this proposal will test the hypothesis that cardiac GLP-1R stimulation activates PPARα resulting in decreased metabolic stress-induced apoptosis, fibrosis and increased β-oxidation and is the mechanism for cardiac recovery after SG. This award will produce a detailed understanding of cardiovascular pathophysiology, myocyte intracellular signaling pathways, biochemistry, and cardiac function analysis needed by the applicant. Further, this proposal allows for a rigorous training program to acquire the skills necessary to become a successful independent investigator with the mentorship of Dr. Corbett and the advisory committee. The primary goal of this mentored career development award is to determine the mechanisms for improved cardiac function after bariatric surgery and produce the preliminary studies needed to achieve extramural support via investigator initiated R01 funding by the NIH. The long-term scientific objective is to understand the mechanisms of interaction between bariatric surgery, obesity, and heart failure and translate these findings into surgical and non-surgical metabolic interventions. The Medical College of Wisconsin (MCW) provides an excellent environment for translational cardiovascular research. MCW's Cardiovascular Center and Clinical and Translational Science Institute provide excellent core resources and a strong collaborative environment to successfully perform the proposed studies and develop strong independent lines of investigation.

项目概要肥胖型心肌病是一种日益流行的心肌细胞功能障碍性疾病由于严重肥胖而导致的心力衰竭即使通过节食减轻体重也无法改善心脏功能。功能，通过减肥手术（如袖状胃切除术 (SG)）治疗肥胖可显着改善心脏功能 SG 后心脏恢复的刺激机制尚不清楚。心脏胰高血糖素样肽 1 受体 (GLP-1R) 信号转导导致激活的新假设核受体过氧化物酶体增殖物激活受体α（PPARα），导致心脏功能改善申请人发现，在肥胖大鼠中进行的 SG 显着改善了心脏功能，与体重减轻无关，与血清 GLP-1 增加、心脏 PPARα 增加和减少有关该提案的具体目标将测试心脏细胞凋亡、纤维化和底物利用的变化。假设心脏 GLP-1R 刺激激活 PPARα，导致代谢应激诱导的减少细胞凋亡、纤维化和β-氧化增加是 SG 后心脏恢复的机制。将详细了解心血管病理生理学、心肌细胞内信号传导此外，该提案还考虑了申请人所需的途径、生物化学和心脏功能分析。严格的培训计划，以获得成为一名成功的独立调查员所需的技能 Corbett 博士和咨询委员会的领导是这一指导职业的主要目标。开发奖旨在确定减肥手术后改善心脏功能的机制通过研究者发起的 R01 资助，开展获得校外支持所需的初步研究 NIH 的长期科学目标是了解减肥之间的相互作用机制。手术、肥胖和心力衰竭，并将这些发现转化为手术和非手术代谢威斯康星医学院 (MCW) 为转化提供了良好的环境。 MCW 的心血管中心和临床与转化科学研究所提供心血管研究。优秀的核心资源和强大的协作环境可成功开展拟议的研究并建立强有力的独立调查线。