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

项目总结/摘要 心血管疾病是2型糖尿病患者发病和死亡的主要原因 （T2DM）。确定T2 DM治疗的心血管效应具有临床重要性。人类遗传学可能 作为一种策略，为T2 DM治疗的长期效应和T2 DM与 心血管风险二肽基肽酶4（DPP 4）抑制剂用于治疗T2 DM， 降解可能具有代谢或心血管效应的底物，如胰高血糖素样肽-1 （GLP-1）、神经肽、CXCL 12、脑利钠肽和P物质。 通过GLP-1作用改善葡萄糖动力学，DPP 4抑制剂也与增加的 因心力衰竭住院治疗（如沙格列汀治疗期间），可能与以下不良反应相关 神经肽，CXCL 12和P物质。关于DPP 4抑制的心血管效应的长期数据仍然存在 由于DPP 4抑制剂的最长心血管结局试验仅为3年，因此该研究受到限制。我们的初步 宾夕法尼亚大学医学生物库中的个体数据显示，对罕见的基因丢失的基因负担分析显示， 功能变异，DPP 4功能丧失与心力衰竭显著相关。表型个体 与DPP 4功能丧失的关系将为这一发现的可能机制提供进一步的见解， 在人类中降低DPP 4活性和抗原的长期效应。 我们推测，遗传性DPP 4功能丧失与代谢改善有关。 参数，但也与心力衰竭和相关的生物标志物/成像。我们将在宾夕法尼亚大学 使用DPP 4功能缺失变体及其匹配对照的医学生物库，并招募他们进行研究。 表型研究我们还将招募参与者进行试点临床试验，以评估个人的反应 DPP 4功能丧失对药物DPP 4抑制的杂合子。 候选人拥有强大的多学科指导团队，其中包括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。候选人将获得必要的技能和专业知识，在奖励期间， 领域：遗传学，基于遗传学的临床试验招募方法，胰岛素的数学建模 敏感性和胰岛素分泌，先进的生物统计学和领导技能。这将有助于候选人 实现必要的里程碑，成为一个独立的学术物理学家，科学家，专门从事 使用遗传学和临床试验方法回答T2 DM和代谢、心血管 风险和相关治疗。

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.