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

描述(由申请者提供)：这份K99/R00培训申请将为Halade博士向独立的NCCAM研究人员过渡提供培训和研究时间。该项目的培训目标是获得更多的心脏生物学经验，使Halade博士能够过渡到独立的职业生涯，专注于使用营养和替代医学方法来改善心血管健康。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战略，心脏生理学的额外课程作业，以及在研讨会和期刊俱乐部的演讲。首席调查员得到了他的导师和职业发展咨询委员会的大力支持，该委员会由各自领域的主要专家组成。本课题的研究目标是研究二十二碳六烯酸(DHA)对心肌梗死(MI)后肿瘤坏死因子-1信号转导通路的抗炎作用。我将使用一种独特的衰老小鼠模型，从中年开始，喂食n-6脂肪酸(玉米油)饮食六个月，以诱导肥胖。DHA的作用将与肿瘤坏死因子-1拮抗剂(依那西普)进行比较。我将测试中心假设，即DHA通过钝化肿瘤坏死因子-1介导的炎症和细胞外基质转换来减轻心肌梗死后的心脏重塑。为了验证我们的假设，我将：1)测试DHA是否通过钝化肿瘤坏死因子-1介导的炎症和细胞外基质转换来减轻MI后的心脏重塑；2)确定DHA是否减轻MI诱导的成纤维细胞激活；3)确定DHA是否减弱MI诱导的巨噬细胞激活。我的翻译和临床相关假设适用于影响深远的肥胖症流行，在肥胖症中，心血管疾病是一种可以接受营养补充的主要并发症。我将使用综合生理学、细胞生物学、生物化学、质谱学和组织学方法的多学科方法，揭示衰老和肥胖如何通过成纤维细胞和巨噬细胞的激活状态影响左室重构过程的机制。这个应用程序的创新之处在于，我将使用：1)鱼油成分，以分配单个组成功能；2)从中年开始喂食高n-6脂肪酸饮食的小鼠，它更接近于人类；3)最先进的方法，使我能够发展成为一名独立的研究人员。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。

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.