Mentored Patient Oriented Research in Cardiometabolic Disease

描述（由申请人提供）：项目摘要赖利博士在宾夕法尼亚大学（Penn）的独特机械患者导向研究（POR）和指导方面有着良好的记录。他的心脏代谢研究计划致力于动脉粥样硬化性心血管疾病（ASCVD）及其危险因素的人类翻译和基因组研究。他的计划是基于宾夕法尼亚大学的心血管和转化研究所，并高度整合到由宾夕法尼亚大学的临床和转化科学奖赞助的培训任务。这为翻译POR和指导K24学员提供了出色的环境。他有一个持续的NIH资金，在翻译POR多名医生科学家的导师，和许多高影响力的翻译出版物，由十几名学员，其中几个已经建立了自己的独立POR职业领导的跟踪记录。赖利博士认识到将基础科学和尖端转化技术纳入POR学术生涯的挑战。他致力于培训年轻的临床研究人员在这些方法和指导他们在POR独立的职业生涯。在本申请中，他建议（1）增强其科学和指导技能，并将更多时间用于机械POR，（2）在指导新临床研究者进行机械POR方面提供更多时间和结构，以及（3）追求新的创新POR，以便为指导年轻临床研究者提供独特的培训环境和POR框架。 尽管最近的基因组发现已经确定了与ASCVD及其危险因素的新关联，但关键挑战仍然是证明这些基因座如何导致疾病，并可用于临床应用和治疗靶向。拟议中的K24研究将招募健康人从脂肪组织活检中产生诱导多能干细胞（iPS）。iPS细胞将用于解决试点研究心脏病基因组最新发现的组织特异性功能研究，（a）SORT 1，一种新的LDL-胆固醇和心肌梗死位点，调节肝细胞脂蛋白，（B）ABO，一种风险内皮风险生物标志物和心肌梗死位点，调节内皮分泌蛋白。Reilly博士将通过减少行政和临床职责，将40%的精力投入到K24提案中（5%用于增强他的指导和POR技能; 10%用于研究提案; 25%用于指导新研究者）。K24奖提供了理想的机制，以扩大他的机械POR计划，同时致力于培养年轻的临床研究人员的重大努力。

DESCRIPTION (provided by applicant): Project Summary Dr. Reilly has a track record in unique mechanistic patient oriented research (POR) and mentorship at the University of Pennsylvania (Penn). His Cardiometabolic Research Program is dedicated to human translational and genomic studies of atherosclerotic cardiovascular disease (ASCVD) and its risk factors. His program is based in Penn's Cardiovascular and Translational Institutes and highly integrated into the training missions sponsored by Penn's Clinical and Translational Science Award. This provides an outstanding environment for translational POR and for mentoring K24 trainees. He has had a track record of continuous NIH funding, mentorship of multiple physician scientists in translational POR, and numerous high-impact translational publications led by over a dozen trainees, several of whom have established their own independent POR careers. Dr Reilly recognizes the challenges to incorporating basic science and cutting edge translational technologies into academic careers in POR. He is committed to training young clinical investigators in these approaches and mentoring them to independent careers in POR. In this application, he proposes to (1) augment his scientific and mentoring skills and devote more time to mechanistic POR, (2) provide increased time and structure in mentoring new clinical investigators in the conduct of mechanistic POR, and (3) pursue new innovative POR in order to provide a unique training environment and POR framework for mentoring young clinical investigators. Although recent genomic discoveries have identified novel associations with ASCVD and its risk factors, the key challenge remains in demonstrating how these loci cause disease and can be advanced for clinical application and therapeutic targeting. The proposed K24 research will recruit healthy humans to generate induced pluripotent stem (iPS) cells from adipose tissue biopsies. The iPS cells will be used to address pilot studies tissue-specific functional studies of recent genomic discoveries for heart disease, (a) SORT1, a novel LDL-cholesterol and myocardial infarction locus, in regulation of hepatocyte lipoproteins and, (b) ABO, a locus for risk endothelial risk biomarkers and myocardial infarction, in regulation of endothelial secreted proteins. Dr Reilly will dedicate 40% effort to this K24 proposal (5% to augment his mentorship and POR skills; 10% to the research proposal; and 25% to mentoring new investigators) through reduction in administrative and clinical duties. The K24 award provides the ideal mechanism to expand his mechanistic POR program while simultaneously dedicating significant effort to train young clinical investigators.