META - Mentor, Educate, Train, Advocate: Patient Oriented Researchers in Cardiometabolic Disease

项目摘要 博士Latha Palaniappan，MD，MS是一位公认的临床研究人员，拥有长期的资金记录， 专业知识，并指导以患者为导向的研究（POR）在心脏代谢疾病。作为一名新上任的 斯坦福大学医学教授，她丰富的临床研究和教学经验将有助于 她的导师和培训下一代临床和转化科学家在POR。虽然帕拉尼亚潘博士 目前是两个NIH资助的临床试验的首席研究员，她正在寻求支持，以追求新的 心脏代谢健康的机制研究方向，特别是在正常体重的2型糖尿病患者中 糖尿病，影响超过300万美国人，并与较高的心血管死亡率相关。在 此外，这项K24提案将利用Palaniappan博士的广泛经验来提供创新且 在POR中培训学员的动态设置。她的学员可以利用现有的研究平台 通过两项大型随机临床试验（RCT），即STRONG-D（正常体重）和IMPACT （超重/肥胖）和现有的机构生物库（斯坦福大学GenePool）。这些生物库样本将 为她未来的研究方向提供基础，该方向将侧重于心脏代谢的机制差异， 三组健康状况：正常体重糖尿病患者（STRONG-D）、超重/肥胖（IMPACT） 糖尿病个体和正常体重血糖正常个体（斯坦福大学GenePool）。她会用 人诱导多能干细胞、代谢组学和外泌体分析。具体目标如下： 目的1：表征三组的心脏代谢健康（每组n=40）。我们假设 正常体重的糖尿病患者（NWD）心脏代谢最不健康，其次是超重/肥胖 PWD，然后是正常体重的正常人。 目的2：研究人类诱导多能干细胞（iPSC）的功能差异，特别是在 心肌细胞和内皮细胞（每组n=3）。我们假设个体 对于正常体重的糖尿病患者，心肌细胞将表现出更多的功能障碍（心脏收缩力降低）， 内皮细胞（较少的一氧化氮输出）。 目的3：检查三组的代谢产物谱（每组n=40）。我们假设NWD将 比超重或肥胖的糖尿病患者有更多的肝脏新生代谢物。 目的4：评估和比较三组中的外泌体概况（每组n=40）。我们假设 NWD将比超重/肥胖糖尿病患者表达更多的抗血管生成miRNA（miR-320）， 控制体重。 该提案将确定新的干预途径，以预测，预防和治疗死亡率和发病率， 正常体重糖尿病

PROJECT SUMMARY Dr. Latha Palaniappan, MD, MS is a well-recognized clinical researcher with a long track record of funding, expertise, and mentoring in patient-oriented research (POR) in cardiometabolic disease. As a newly-appointed Professor of Medicine at Stanford University, her extensive clinical research and teaching experience will help her mentor and train the next generation clinical and translational scientists in POR. Although Dr. Palaniappan is currently the lead investigator of two NIH-funded clinical trials, she is seeking support to pursue novel mechanistic research directions in cardiometabolic health, particularly in adults of normal weight with Type 2 diabetes, which affects over 3 million Americans and is associated with higher cardiovascular mortality. In addition, this K24 proposal will leverage Dr. Palaniappan’s breadth of experience to provide an innovative and dynamic setting to train mentees in POR. Her mentees can leverage the existing research platform available through two large, randomized clinical trials (RCTs), namely STRONG-D (normal weight) and IMPACT (overweight/obese), and an existing institutional biobank (Stanford GenePool). These biobanked samples will provide the basis for her future research direction which will focus on mechanistic differences in cardiometabolic health in three groups: normal-weight patients with diabetes (STRONG-D), overweight/obese (IMPACT) individuals with diabetes, and normal weight normoglycemic individuals (Stanford GenePool). She will use human induced pluripotent stem cells, metabolomics, and exosome profiling. The Specific Aims are as follows: Aim 1: Characterize cardiometabolic health across the three groups (n=40 in each group). We hypothesize that normal-weight people with diabetes (NWD) will be most cardiometabolically unhealthy followed by overweight/obese PWDs, followed by normal-weight normoglycemia. Aim 2: Investigate the functional differences in human induced pluripotent stem cells (iPSCs), specifically in cardiomyocytes and endothelial cells across the three groups (n=3 in each group). We hypothesize that individuals with normal weight diabetes will exhibit more dysfunction in cardiomyocytes (less cardiac contractility) and endothelial cells (less nitric oxide output). Aim 3: Examine metabolite profiles across the three groups (n=40 in each group). We hypothesize that NWDs will have more hepatic gluconeogenesis metabolites than overweight or obese individuals with diabetes. Aim 4: Evaluate and compare exosome profiles across the three groups (n=40 in each group). We hypothesize that NWDs will express more anti-angiogenesis miRNAs (miR-320) than overweight/obese individuals with diabetes after controlling for weight. This proposal will identify new pathways for intervention to predict, prevent and treat mortality and morbidity in normal weight diabetes.