DHA Mechanisms in Obesity-mediated Cardiac Remodeling Post-Myocardial Infarction

DHA 在肥胖介导的心肌梗死后心脏重塑中的机制

• 批准号: 8165292
• 负责人: Ganesh V Halade
• 金额: $ 9.72万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165292
• 关键词: Advisory Committees; Affect; Age-Months; Aging; Alternative Medicine; American; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Attenuated; Back; Biochemistry; Biology; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cellular biology; Chronic; Complication; Corn Oil; Diabetes Mellitus; Diagnosis; Diet; Discipline; Docosahexaenoic Acids; Echocardiography; Eicosapentaenoic Acid; Epidemic; Etanercept; Extracellular Matrix; Fatty Acids; Fatty acid glycerol esters; Fibroblasts; Fish Oils; Gene Expression; Gene Proteins; Goals; Health; Health Sciences; Histology; Human; Hyperglycemia; Immunoblotting; Individual; Inflammation; Inflammatory; Insulin Resistance; Journals; Left Ventricular Remodeling; Life; Link; Lupus; Macrophage Activation; Mass Spectrum Analysis; Measures; Mediating; Mentors; Modeling; Molecular; Mus; Myocardial Infarction; National Center for Complementary and Alternative Medicine; Nutritional; Obese Mice; Obesity; Omega-3 Fatty Acids; Pathway interactions; Pattern; Phase; Physiological; Physiology; Principal Investigator; Process; Property; Protein Secretion; Proteomics; Research; Research Personnel; Research Training; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Signal Pathway; Signal Transduction; Structure; Supplementation; TNF gene; Testing; Texas; Time; Training; Universities; Ventricular; career; career development; clinically relevant; dietary supplements; experience; feeding; improved; innovation; interest; macrophage; middle age; mouse model; response

DESCRIPTION (provided by applicant): This K99/R00 training application will provide training and research time for Dr. Halade's transition to independence as an NCCAM-focused investigator. The training goal of this project is to obtain additional experience in cardiac biology to allow Dr. Halade to transition to an independent career focused on using nutritional and alternative medicine approaches to improve cardiovascular health. The training plan will be carried out at the University of Texas Health Science Center at San Antonio, and includes individual and team mentoring strategies, additional coursework in cardiac physiology, and presentations at seminars and journal clubs. The principal investigator is strongly supported by his mentor and career development advisory committee that is composed of leading experts in their respective fields. The research goal of this project is to study the anti-inflammatory effect of docosahexaenoic acid (DHA) on TNF-1 signaling following myocardial infarction (MI). I will use a unique model of aging mice that have been fed an n-6 fatty acids (corn oil) diet for six months, beginning at middle-age, to induce obesity. DHA effects will be compared to a TNF-1 antagonist (etanercept). I will test the central hypothesis that DHA attenuates cardiac remodeling following MI by blunting TNF-1-mediated inflammation and extracellular matrix turnover. To test our hypotheses I will: 1) test whether DHA attenuates cardiac remodeling following MI by blunting TNF-1-mediated inflammation and extracellular matrix turnover 2) determine whether DHA attenuates fibroblast activation induced by MI 3) determine whether DHA attenuates macrophage activation induced by MI. My translational and clinically relevant hypothesis has applicability to the far-reaching epidemic of obesity, in which cardiovascular disease is a primary complication amenable to nutritional supplementation. I will use a multi-discipline approach that integrates physiology, cell biology, biochemistry, mass spectrometry, and histological approaches to unveil mechanisms on how aging and obesity influence the LV remodeling process as a function of fibroblast and macrophage activation status. The innovation of this application is that I will use: 1) components of fish oil in order to assign individual constituent functions; 2) mice that are fed high n- 6 fatty acids diet beginning at middle-age, which more closely mimics what is seen in humans; and 3) state of the art approaches that will allow me to develop as an independent investigator. The results of these studies will clarify the role of DHA in post-MI remodeling in the setting of aging and obesity. PUBLIC HEALTH RELEVANCE: Fish oil is the most commonly used dietary supplement and is composed of both docosahexaenoic acid (DHA) and eicosapentaenoic acid. Over 1.2 million Americans are diagnosed with a heart attack each year, and obesity is a primary risk factor for cardiovascular disease. This project will define how the individual component DHA affects, how an aging and obese mouse responds to a heart attack.

描述（由申请人提供）：此 K99/R00 培训申请将为 Halade 博士过渡到独立作为 NCCAM 重点研究人员提供培训和研究时间。 该项目的培训目标是获得心脏生物学方面的额外经验，使哈拉德博士能够过渡到专注于使用营养和替代医学方法来改善心血管健康的独立职业。该培训计划将在圣安东尼奥的德克萨斯大学健康科学中心进行，包括个人和团队指导策略、心脏生理学的额外课程以及在研讨会和期刊俱乐部的演讲。首席研究员得到了导师和由各自领域的顶尖专家组成的职业发展咨询委员会的大力支持。 该项目的研究目标是研究二十二碳六烯酸（DHA）对心肌梗塞（MI）后TNF-1信号传导的抗炎作用。我将使用一种独特的衰老小鼠模型，这些小鼠从中年开始被喂食 n-6 脂肪酸（玉米油）六个月，以诱导肥胖。 DHA 的作用将与 TNF-1 拮抗剂（依那西普）进行比较。我将检验以下中心假设：DHA 通过减弱 TNF-1 介导的炎症和细胞外基质更新来减轻 MI 后的心脏重塑。为了检验我们的假设，我将： 1) 测试 DHA 是否通过减弱 TNF-1 介导的炎症和细胞外基质周转来减弱 MI 后的心脏重塑 2) 确定 DHA 是否减弱 MI 诱导的成纤维细胞活化 3) 确定 DHA 是否减弱 MI 诱导的巨噬细胞活化米。 我的转化和临床相关假设适用于影响深远的肥胖流行病，其中心血管疾病是营养补充的主要并发症。我将采用整合生理学、细胞生物学、生物化学、质谱和组织学方法的多学科方法来揭示衰老和肥胖如何影响左室重塑过程（作为成纤维细胞和巨噬细胞激活状态的函数）的机制。该应用程序的创新之处在于，我将使用：1）鱼油成分，以便分配各个组成功能； 2）从中年开始喂食高n-6脂肪酸饮食的小鼠，这更接近于人类的饮食； 3）最先进的方法，使我能够成为一名独立调查员。这些研究的结果将阐明 DHA 在衰老和肥胖背景下心肌梗死后重塑中的作用。 公共健康相关性：鱼油是最常用的膳食补充剂，由二十二碳六烯酸 (DHA) 和二十碳五烯酸组成。每年有超过 120 万美国人被诊断患有心脏病，而肥胖是心血管疾病的主要危险因素。该项目将定义 DHA 的各个成分如何影响，以及衰老和肥胖的小鼠如何应对心脏病发作。