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

项目总结 Latha Palaniappan博士，医学博士，医学硕士，是一位公认的临床研究人员，有着长期的资助记录， 以患者为中心的心脏代谢性疾病研究(POR)方面的专业知识和指导。作为一名新任命的 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 她指导和培训了POR领域的下一代临床和翻译科学家。尽管帕拉尼亚潘博士 目前是美国国立卫生研究院资助的两项临床试验的首席研究员，她正在寻求支持，以追求新颖 心脏代谢健康的机制研究方向，特别是2型正常体重的成年人 糖尿病影响了300多万美国人，并与更高的心血管死亡率有关。在……里面 此外，这项K24计划将利用Palaniappan博士的丰富经验提供创新和 对学员进行POR培训的动态设置。她的学员可以利用现有的研究平台 通过两个大型随机临床试验(RCT)，即Strong-D(正常体重)和Impact (超重/肥胖)和现有的机构生物库(斯坦福基因库)。这些生物库样本将 为她今后的研究方向提供了基础，重点是心脏代谢的机制差异 健康三组：正常体重糖尿病患者(STRONG-D)、超重/肥胖患者(IMPACT) 糖尿病患者和体重正常的血糖正常的个人(斯坦福遗传池)。她会用 人类诱导多能干细胞、代谢组学和外切体谱。具体目标如下： 目的1：研究三组(每组40例)的心脏代谢健康状况。我们假设 体重正常的糖尿病(NWD)患者的心脏代谢最不健康，其次是超重/肥胖 残障，然后是正常体重的正常血糖。 目的2：研究人诱导多能干细胞(IPSCs)的功能差异 三组心肌细胞和内皮细胞(每组n=3)。我们假设每个人 体重正常的糖尿病会表现出更多的心肌细胞功能障碍(心肌收缩能力降低)和 内皮细胞(一氧化氮产量较少)。 目的3：检查三组(每组40例)的代谢物分布。我们假设NWDS会 比超重或肥胖的糖尿病患者有更多的肝糖异生代谢产物。 目的4：评估和比较三组(每组40例)的外切体谱。我们假设 与超重/肥胖的糖尿病患者相比，NWD将表达更多的抗血管生成miRNAs(miR-320) 控制体重。 这项建议将确定新的干预途径，以预测、预防和治疗#年的死亡率和发病率 体重正常的糖尿病。

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.