DGAT1 Mediated Cardiac Steatosis

DGAT1 介导的心脏脂肪变性

• 批准号: 7740669
• 负责人: DENIS J GLENN
• 金额: $ 12.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740669
• 关键词: Acyl Coenzyme A; Address; Adipose tissue; Affect; Animal Model; Biology; California; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cardiovascular system; Complication; Deacetylase; Deposition; Development; Diabetes Mellitus; Diet; Doctor of Philosophy; Ensure; Environment; Enzymes; Event; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Functional disorder; Genes; Genomics; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertriglyceridemia; Hypertrophy; Instruction; Intervention; Kidney; Lead; Lipids; Liver; Mediating; Mentors; Mentorship; Metabolic; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Muscle Cells; Myocardial Ischemia; Myocardium; Obesity; Overnutrition; Prevalence; Principal Investigator; Process; Research; Research Personnel; Research Proposals; Research Training; Resveratrol; Risk; Risk Factors; Role; San Francisco; Skeletal Muscle; Stress; Testing; Tissues; Training; Transgenic Mice; Transgenic Model; Transgenic Organisms; Triglycerides; Universities; abstracting; advanced disease; cardiovascular disorder risk; design; diabetic; diabetic cardiomyopathy; diacylglycerol O-acyltransferase; experience; heart function; lipid metabolism; mitochondrial dysfunction; mouse model; overexpression; patient population; programs; skills; success; transcription factor

DESCRIPTION (provided by applicant): This application for Denis Glenn M.D.,Ph.D. describes a five year strategy designed to enhance his research and professional skills with the ultimate goal of transitioning to an independent, academic investigator in the field of renal and cardiovascular biology. The research proposal seeks to understand the role of the enzyme, diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the final step in triglyceride synthesis, in the heart. DGAT activity and expression have been shown to be increased in animal models of diabetes and ischemic heart disease. However, it remains unclear if enhanced DGAT1 activity and the resulting lipid accumulation in the heart are pathogenic. To begin to address this question a cardiac selective DGAT1 transgenic mouse has been created and preliminary results suggest that DGAT1 over expression results in cardiac dysfunction. The first aim will define the role of neutral lipid deposition as a risk factor for the development of cardiac dysfunction in the cardiac DGAT1 transgenic mouse subjected to high fat diet and pharmacologically induced cardiac hypertrophy. Initial characterization of this mouse has revealed.a reduction in expression of the deacetylase SIRT1 and the second aim will explore the role of SIRT1 and PGC1 alpha in mediating the effects of lipid deposition and cardiac myocyte dysfunction. The mentored research and training plan will provide experience in development of mouse models of disease, advanced training in cardiovascular assessment in the mouse and professional skills development. The mentor. Dr. David Gardner is an expert in the field of cardiovascular and renal research and will continue to advise both scientifically and professionally. In addition, a scientific advisory and mentorship committee of experts in the fields of cardiovascular, renal and lipid metabolism has been assembled to aid in the training and research plan and will track professional progress to help ensure progression towards the goal of becoming an independent investigator. The project will be carried out at the University of California, San Francisco which provides an outstanding environment in which to conduct this research and develop the professional skills critical to the success of a young investigator. [RELEVANCE (See instructions): Obesity and the complications of overnutrition are increasingly important issues, as the prevalence of obesity is increasing globally. The major complication associated with obesity is the development of DM with the attendant increased risk of cardiovascular disease and heart failure. This application seeks to explore the role of lipid deposition in contributing to cardiac dysfunction and may provide important information which will help to irientifv molecular targets that mav prove amenahlfi tn thfiraheutic intervention. (End of Abstract)

描述（由申请人提供）：这份申请申请丹尼斯·格伦医学博士。描述了一个五年的战略，旨在提高他的研究和专业技能，最终目标是过渡到一个独立的，学术研究者在肾脏和心血管生物学领域。该研究计划旨在了解二酰基甘油酰基转移酶1 （DGAT1）在心脏中的作用，该酶催化甘油三酯合成的最后一步。在糖尿病和缺血性心脏病的动物模型中，DGAT的活性和表达均有所增加。然而，目前尚不清楚DGAT1活性增强和由此导致的心脏脂质积累是否具有致病性。为了开始解决这个问题，一个心脏选择性DGAT1转基因小鼠已经被创建，初步结果表明DGAT1过表达导致心功能障碍。第一个目标是确定中性脂质沉积在高脂肪饮食和药理学诱导的心脏肥厚的DGAT1转基因小鼠心脏中作为心功能障碍发展的危险因素的作用。这只老鼠的初步特征已经揭示。去乙酰化酶SIRT1的表达减少，第二个目标将探索SIRT1和PGC1 α在介导脂质沉积和心肌细胞功能障碍中的作用。指导的研究和培训计划将提供开发疾病小鼠模型的经验，小鼠心血管评估的高级培训和专业技能发展。的导师。David Gardner博士是心血管和肾脏研究领域的专家，他将继续提供科学和专业的建议。此外，一个由心血管、肾脏和脂质代谢领域的专家组成的科学咨询和指导委员会已经成立，以协助培训和研究计划，并将跟踪专业进展，以帮助确保朝着成为独立研究者的目标前进。该项目将在加州大学旧金山分校进行，该大学为开展这项研究和培养对年轻研究者成功至关重要的专业技能提供了良好的环境。[相关性（见说明）：随着全球肥胖患病率的上升，肥胖和营养过剩并发症日益成为重要问题。与肥胖相关的主要并发症是糖尿病的发展以及随之而来的心血管疾病和心力衰竭的风险增加。本应用程序旨在探索脂质沉积在心功能障碍中的作用，并可能提供重要信息，有助于识别可能证明在治疗干预中具有重要作用的分子靶点。（摘要结束）