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

基因减少的二肽基肽酶 4 (DPP4) 对心脏代谢的影响（来自 UPENN 的资助）

基本信息

批准号：
10548188
负责人：
Jessica Rose Wilson
金额：
$ 16.19万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548188
关键词：
Adipocytes Adult Age Agonist Animal Model Antigens Area Atherosclerosis Award Biological Markers Biometry Body mass index Brain natriuretic peptide Cardiac Cardiology Cardiopulmonary Cardiovascular Diseases Cardiovascular system Catecholamines Cessation of life Chronic 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 Exercise Test Fibroblasts Fibrosis Functional disorder Gadolinium Gender Genes Genetic Glucose Grant Heart failure Hepatic Hepatocyte Heterozygote High Fat Diet High Prevalence Hospitalization Hour Human Human Genetics Hypertension Hypoxia Image Individual Insulin Resistance Leadership Link Lipids Long-Term Effects 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 Patient-Focused Outcomes Patients Peptide Hydrolases Peptide YY Peptides Peptidyl-Dipeptidase A Pharmaceutical Preparations Phenotype Physicians Pilot Projects Placebos Production Proteomics Resistance Risk Sampling Scientist Stromal Cell-Derived Factor 1 Substance P T-Lymphocyte Testing Triglycerides Variant Visceral Weight Weight Gain biobank cardiac magnetic resonance imaging cardiometabolism cardiovascular effects cardiovascular risk factor clinical trial recruitment comparison control coronary fibrosis diabetes mellitus therapy diabetes risk glucagon-like peptide glucagon-like peptide 1 glycemic control improved incretin hormone indexing individual response inhibitor insight insulin secretion insulin sensitivity loss of function mathematical model metabolic phenotype metabolomics monocyte mortality multidisciplinary neuropeptide Y non-alcoholic fatty liver disease participant enrollment patient oriented research peptide P pharmacologic recruit skills tool

项目摘要

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，成为一名专门从事该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。