DGAT1 Mediated Cardiac Steatosis

描述(由申请人提供)：这份申请Denis Glenn医学博士的申请描述了一项为期五年的战略，旨在提高他的研究和专业技能，最终目标是过渡到肾脏和心血管生物学领域的一名独立的学术研究员。这项研究计划试图了解催化甘油三酯合成最后一步的酶--二酰甘油酰基转移酶1(DGAT1)在心脏中的作用。在糖尿病和缺血性心脏病的动物模型中，DGAT的活性和表达都被证明是增加的。然而，目前尚不清楚DGAT1活性增强和由此导致的心脏脂质堆积是否是致病的。为了开始解决这个问题，已经建立了心脏选择性DGAT1转基因小鼠，初步结果表明DGAT1过度表达会导致心功能障碍。第一个目标将确定中性脂肪沉积作为心脏DGAT1转基因小鼠心脏功能障碍的危险因素在高脂饮食和药物诱导的心肌肥厚中的作用。这只小鼠的初步特征表明：脱乙酰酶SIRT1的表达减少，第二个目的是探索SIRT1和PGC1α在介导脂质沉积和心肌细胞功能障碍中的作用。指导研究和培训计划将提供开发老鼠疾病模型的经验，在老鼠心血管评估和专业技能发展方面的高级培训。导师。大卫·加德纳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，已经组建了一个由心血管、肾脏和脂类代谢领域的专家组成的科学咨询和指导委员会，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调查员的目标前进。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调查员的成功至关重要的专业技能提供了一个出色的环境。[相关性(见说明)：肥胖和营养过剩的并发症是日益重要的问题，因为全球肥胖率正在上升。与肥胖相关的主要并发症是糖尿病的发展，伴随而来的是心血管疾病和心力衰竭风险的增加。本申请旨在探索脂质沉积在导致心功能不全中的作用，并可能提供重要信息，有助于筛选MAV在心脏干预中证明有效的分子靶点。(摘要结束)

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)