Mentored Patient Oriented Research in Cardiometabolic Disease

描述(由申请者提供)：项目摘要Reilly博士在宾夕法尼亚大学(宾夕法尼亚大学)独特的机械化患者导向研究(POR)和指导方面有着良好的记录。他的心脏代谢研究项目致力于人类动脉粥样硬化性心血管疾病(ASCVD)及其危险因素的翻译和基因组研究。他的项目设在宾夕法尼亚大学的心血管和翻译学院，并高度融入宾夕法尼亚大学临床和翻译科学奖赞助的培训任务中。这为翻译POR和指导K24实习生提供了一个出色的环境。他有连续资助NIH的记录，在翻译POR方面指导过多名内科科学家，并由十几名学员领导的许多高影响力的翻译出版物，其中几人已经建立了自己的POR职业生涯。赖利博士认识到将基础科学和尖端翻译技术融入POR的学术生涯中所面临的挑战。他致力于培训年轻的临床研究人员使用这些方法，并指导他们在POR中从事独立的职业生涯。在这项申请中，他建议(1)增强他的科学和指导技能，并将更多的时间投入到机械式POR上，(2)在进行机械式POR时提供更多的时间和结构来指导新的临床研究人员，以及(3)追求新的创新POR，以便为指导年轻的临床研究人员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发现了与ASCVD及其危险因素的新关联，但关键的挑战仍然是如何证明这些基因座如何导致疾病，并可推进临床应用和治疗靶向。拟议的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细胞将用于对近期发现的心脏病基因组的组织特异性功能研究的初步研究，(A)SORT1，一种新的低密度脂蛋白-胆固醇和心肌梗死基因座，调节肝细胞脂蛋白；(B)ABO，血管内皮细胞危险生物标志物和心肌梗死的基因座，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%用于加强他的指导和POR技能；10%用于研究提案；25%用于指导新的研究人员)。K24奖提供了理想的机制来扩大他的机械性POR计划，同时致力于培训年轻的临床研究人员。

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.