Cardiometabolic effects of genetically decreased dipeptidyl peptidase-4 (DPP4)

基因减少的二肽基肽酶 4 (DPP4) 对心脏代谢的影响

• 批准号: 9892612
• 负责人: Jessica Rose Wilson
• 金额: $ 16.19万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892612
• 关键词: Adipocytes; Adult; Age; Agonist; Animal Model; Antigens; Area; Atherosclerosis; Award; Biological Markers; Biometry; Brain natriuretic peptide; CXCL12 gene; Cardiac; Cardiology; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cessation of life; Chronic; Cleaved cell; Clinical; Clinical Trials; Collagen; Data; Development; Diabetes Mellitus; Diffuse Pattern; Dipeptidyl Peptidases; Dipeptidyl-Peptidase IV; Dual-Energy X-Ray Absorptiometry; EFRAC; Echocardiography; Endocrinology; Endothelial Cells; Enrollment; Exercise Test; Fibroblasts; Fibrosis; Functional disorder; Gadolinium; Gender; Genes; Genetic; Glucose; Heart failure; Hepatic; Hepatocyte; High Fat Diet; High Prevalence; Hospitalization; Hour; Human; Human Genetics; Hypertension; Hypoxia; Image; Individual; Insulin Resistance; Lead; Leadership; Link; Lipids; Long-Term Effects; Magnetic Resonance Imaging; Medicine; Mentors; Metabolic; Metabolic Diseases; Metabolism; Morbidity - disease rate; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Oral; Outcome; Outcome Study; Oxygen Consumption; Participant; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Peptide YY; Peptides; Peptidyl-Dipeptidase A; Pharmaceutical Preparations; Pharmacology; Phenotype; Physicians; Pilot Projects; Placebos; Production; Proteomics; Resistance; Risk; Sampling; Scientist; Substance P; T-Lymphocyte; Testing; Time; Triglycerides; Variant; Visceral; Weight; Weight Gain; base; biobank; cardiometabolism; cardiovascular risk factor; case control; coronary fibrosis; diabetes mellitus therapy; diabetes risk; glucagon-like peptide; glucagon-like peptide 1; glycemic control; imaging biomarker; improved; incretin hormone; indexing; individual response; inhibitor/antagonist; insight; insulin secretion; insulin sensitivity; loss of function; mathematical model; metabolic phenotype; metabolomics; monocyte; mortality; multidisciplinary; neuropeptide Y; non-alcoholic fatty liver disease; patient oriented research; peptide P; recruit; skills; tool

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.

项目概要/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 T2DM 治疗对心血管的影响具有重要的临床意义。人类遗传学可能 是一种策略，可以深入了解 T2DM 治疗的长期影响以及 T2DM 与 T2DM 之间的联系机制 心血管风险。二肽基肽酶 4 (DPP4) 抑制剂用于治疗 T2DM 并减少 可能具有代谢或心血管效应的底物降解，例如胰高血糖素样肽-1 (GLP-1)、神经肽、CXCL12、脑钠肽和 P 物质。虽然它们具有以下优点： 通过 GLP-1 效应改善血糖动态，DPP4 抑制剂也与增加的风险相关 因心力衰竭住院（例如沙格列汀治疗期间），可能与以下药物的负面影响有关 神经肽、CXCL12 和 P 物质。DPP4 抑制对心血管影响的长期数据仍然存在 由于 DPP4 抑制剂最长的心血管结局试验只有三年，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个体的数据显示，对罕见损失的基因负荷分析 功能变异，DPP4 功能丧失与心力衰竭显着相关。对个体进行表型分析 DPP4 功能丧失将为这一发现的可能机制提供进一步的见解，并且长期研究 DPP4 活性和抗原降低对人类的长期影响。 我们假设遗传性 DPP4 功能丧失与代谢改善有关 参数，还包括心力衰竭和相关生物标志物/成像。我们将识别宾夕法尼亚州的个人 具有 DPP4 功能缺失变体的医学生物库及其匹配的对照，并招募它们进行 表型研究。我们还将招募参与者参加试点临床试验，以评估个人的反应 DPP4 杂合子导致药物 DPP4 抑制功能丧失。 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。候选人将在颁奖期间获得必要的技能和专业知识 领域：遗传学、基于遗传的临床试验招募方法、胰岛素的数学模型 敏感性和胰岛素分泌、先进的生物统计学和领导技能。这将有利于候选人 实现必要的里程碑，成为一名专门从事以下领域的独立学术医师科学家 使用遗传学和临床试验方法来回答 T2DM 和代谢、心血管等方面的问题 风险和相关治疗。