Cardiometabolic effects of genetically decreased dipeptidyl peptidase-4 (DPP4) (Grant Transfer from UPENN)

项目摘要/摘要 心血管疾病是2型糖尿病患者发病率和死亡率的主要原因。 (T2 DM)。确定T2 DM治疗的心血管效应具有重要的临床意义。人类遗传学可能 作为一项战略，为T2 DM治疗的长期效果和T2 DM与 心血管风险。二肽基肽酶4(DPP4)抑制剂用于治疗2型糖尿病和糖尿病 降解可能对代谢或心血管有影响的底物，如胰高血糖素样肽-1 (GLP-1)、神经肽、CXCL12、脑利钠肽和P物质。 通过GLP-1效应改善血糖动力学，DPP4抑制剂也与增加糖尿病风险有关 因心力衰竭住院(如在萨格列汀期间)，可能与以下药物的负面影响有关 神经肽、CXCL12和P物质。关于DPP4抑制对心血管影响的长期数据仍然存在 作为心血管结局最长的药物，DPP4抑制剂的试验时间仅为三年。我们的预赛 在宾夕法尼亚医学生物库中的个人数据显示，关于基因负担分析的罕见损失 功能变异，DPP4功能丧失与心力衰竭显著相关。表型分型个体 DPP4功能丧失将为这一发现的可能机制提供进一步的见解，并长期- 人类DPP4活性和抗原降低的长期效应。 我们假设遗传性DPP4功能丧失与新陈代谢改善有关 参数，以及心力衰竭和相关的生物标志物/成像。我们会辨认宾夕法尼亚州立大学的 DPP4功能缺失的药物生物库及其匹配的对照，并招募他们进行a 表型研究。我们还将招募参与者参加一项试点临床试验，以评估个人的反应 杂合子导致DPP4功能丧失，导致药理上的DPP4抑制。 候选人拥有一支强大的多学科指导团队，拥有以患者为导向的研究专家， 遗传学、内分泌学、心脏病学(晚期心力衰竭)、数学建模/生物统计学，以及 代谢组学/蛋白质组学。候选人将在获奖期间获得必要的技能和专业知识 研究领域：遗传学，一种基于遗传学的临床试验招募，胰岛素的数学建模 敏感度和胰岛素分泌、高级生物统计学和领导技能。这将为候选人提供便利 取得必要的里程碑，成为一名独立的学术内科医生兼科学家，专门研究 使用遗传学和临床试验方法回答有关T2 DM和新陈代谢、心血管疾病的问题 风险，以及相关的治疗。

PROJECT SUMMARY/ ABSTRACT Cardiovascular disease is the leading cause of morbidity and mortality for patients with type 2 diabetes (T2DM). Determining cardiovascular effects of T2DM therapies is of clinical importance. Human genetics may be a strategy to provide insights to long-term effects of T2DM therapies and mechanisms linking T2DM and cardiovascular risk. Dipeptidyl peptidase 4 (DPP4) inhibitors are used for the treatment of T2DM and decrease degradation of substrates with possible metabolic or cardiovascular effects such as glucagon like peptide-1 (GLP-1), neuropeptides, CXCL12, brain natriuretic peptide, and substance P. Although they have the benefit of improving glucose dynamics through GLP-1 effects, DPP4 inhibitors are also associated with increased risk of hospitalization for heart failure (such as during saxagliptin), potentially related to negative effects of neuropeptides, CXCL12, and substance P. Long-term data on cardiovascular effects of DPP4 inhibition remain limited as the longest cardiovascular outcomes trial of DPP4 inhibitors was only three years. Our preliminary data in among individuals in the Penn Medicine Biobank show that on gene burden analysis for rare loss of function variants, DPP4 loss of function was significantly associated with heart failure. Phenotyping individuals with DPP4 loss of function will provide further insights as to the possible mechanism for this finding and long- term effects of decreased DPP4 activity and antigen in humans. We hypothesize that genetic DPP4 loss of function will be associated with improved metabolic parameters but also with heart failure and related biomarkers/ imaging. We will identify individuals in the Penn Medicine Biobank with DPP4 loss of function variants and their matched controls and recruit them for a phenotyping study. We will also enroll participants in a pilot clinical trial to assess the response of individuals heterozygous for DPP4 loss of function to pharmacologic DPP4 inhibition. The candidate has a strong multi-disciplinary mentoring team with experts in patient oriented research, genetics, endocrinology, cardiology (advanced heart failure), mathematical modeling/ biostatistics, and metabolomics/ proteomics. The candidate will gain necessary skills and expertise during the award period in the areas of: genetics, a genetic-based approach to clinical trials recruitment, mathematical modeling of insulin sensitivity and insulin secretion, advanced biostatistics, and leadership skills. This will facilitate the candidate achieving necessary milestones to become an independent academic physician-scientist specializing in the use of genetics and clinical trials approaches to answer questions in T2DM and metabolism, cardiovascular risk, and related therapies.