Mentoring Patient-Oriented Research in Deep Lipid Phenotyping for Cardiovascular Disease

项目摘要 阿南德·罗哈吉博士是内科/心脏病科副教授 德克萨斯大学西南医学中心。他建立了一个成功的、独立的研究项目 重点阐述了高密度脂蛋白代谢在心血管疾病中的作用。他作为一名积极分子的经历 临床心脏病专家、翻译研究人员和导师将他定位为 K24导师职业发展奖。他的临床重点是预防心脏病学和管理 动脉粥样硬化性疾病的研究为专注于高密度脂蛋白的协同翻译研究计划铺平了道路 新陈代谢和动脉粥样硬化性心血管疾病，以及对指导学员和教职员工的热情。罗哈吉博士有 将流行病学和翻译POR应用于这一目标，导致了一些出版的 在病理生理学的洞察和精细化方面推动了这一领域的观察 高密度脂蛋白相关标记物，用于风险预测和作为治疗目标。这项工作得到了连续 资金来自NIH/NHLBI(K08&GT；R01)、AHA和行业。他还发展了一种重要的 在临床心血管研究和职业发展方面指导学员的专业兴趣。这个 K24奖将支持罗哈吉博士的科学职业活动，允许他从事专业的 通过课程作业/培训和执行新项目来发展，以加强HIS的主要目标 R01，并支持未来的独立资金。除了支持科学事业活动外，K24 该奖项将直接允许Rohatgi博士进行导师/领导力培训，并增强他的能力 与追求K和R01奖项的特定学员深度接触，并更广泛地与所有学员接触 在心血管训练中。这项建议的总体科学目标是：1)确定 影响胆固醇流出可变性的遗传因素；2)确定循环代谢产物和与之相关的蛋白质 胆固醇流出的变化；3)测定低胆固醇与高胆固醇人群中高密度脂蛋白的miRNA含量 外流；4)评估#3中确定的不同miRNAs对胆固醇外流转运体和外流的影响；5) 在那些高密度脂蛋白水平极高的人中，确定是否存在已知的 与升高的高密度脂蛋白胆固醇(SR-B1、CETP、LIPG)和Lp(A)水平相关；6)确定蛋白质组和脂肪组 高密度脂蛋白胆固醇极端升高人群中高密度脂蛋白组分的特征和功能 基因突变和Lp(A)水平升高；7)决定了高密度脂蛋白功能指标之间的关系 (胆固醇流出、高密度脂蛋白颗粒数、载脂蛋白AI)与冠状动脉CT高危斑块的关系 在低风险队列中进行成像。

Project Summary Dr. Anand Rohatgi is an Associate Professor in the Department of Internal Medicine/Division of Cardiology at UT Southwestern Medical Center. He has established a successful and independent research program focused on elucidating the role of HDL metabolism in cardiovascular disease. His experiences as an active clinical cardiologist, translational researcher, and mentor have positioned him to be an ideal candidate for the K24 Mentoring Career Development Award. His clinical focus on preventive cardiology and the management of atherosclerotic disease have paved the way for a synergistic translational research program focused on HDL metabolism and atherosclerotic CV disease and a passion for mentoring trainees and faculty. Dr. Rohatgi has applied both epidemiologic and translational POR to this objective, resulting in a number of published observations that have moved the field forward with respect to insights into pathophysiology and refinement of HDL-related markers for risk prediction and as targets of therapy. This work has been supported by continuous funding from the NIH/NHLBI (K08>R01), the AHA, and industry. He has also developed a significant professional interest in mentoring trainees in clinical cardiovascular research and career development. The K24 award will support Dr. Rohatgi’s scientific career activities by allowing him to engage in professional development via coursework/training and execution of novel projects that will enhance the primary aims of his R01 and support future independent funding. In addition to supporting scientific career activities, the K24 award will directly allow Dr. Rohatgi to pursue mentorship/leadership training and enhance his ability to more deeply engage with specific mentees pursuing K and R01 awards and more broadly engage with all mentees in cardiovascular training. The overall scientific aims of this proposal are to: 1) Determine the contribution of genetic factors to variability in cholesterol efflux; 2) Identify circulating metabolites and proteins linked to variation in cholesterol efflux; 3) Determine the miRNA cargo of HDL in those with low versus high cholesterol efflux; 4) Assess the effect of distinct miRNAs identified in #3 on cholesterol efflux transporters and efflux; 5) Among those with extreme elevation in HDL-C, determine the presence of genetic mutations known to correlate with elevated HDL-C (SR-B1, CETP, LIPG) and Lp(a) levels; 6) Determine proteomic and lipidomic signature and functionality of HDL fractions in those with extreme elevations in HDL-C stratified by presence of genetic mutations and elevated Lp(a) levels; 7) Determine the relationship between HDL function measures (cholesterol efflux, HDL particle number, Apo-AI) and high-risk coronary plaque assessed by coronary CT imaging in low risk cohorts.