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 （T2DM）。确定T2DM疗法的心血管效应至关重要。人类遗传学可能 成为一种策略，以洞悉T2DM疗法的长期影响和连接T2DM和的机制 心血管风险。二肽基肽酶4（DPP4）抑制剂用于治疗T2DM并减少 具有代谢或心血管效应的底物降解，例如胰像肽1 （GLP-1），神经肽，CXCL12，脑脂肪肽和物质P。 通过GLP-1效应改善葡萄糖动力学，DPP4抑制剂也与增加 心力衰竭的住院治疗（例如在萨克拉列汀期间），可能与 神经肽，CXCL12和物质P.关于DPP4抑制心血管效应的长期数据仍然存在 受到DPP4抑制剂最长的心血管结局试验的限制只有三年。我们的初步 宾夕法尼亚医学生物库中个体中的数据表明，在基因负担分析中，很少损失 功能变异，DPP4功能丧失与心力衰竭显着相关。表型个体 随着DPP4功能的损失，将为这一发现的可能机制提供进一步的见解 人类DPP4活性和抗原降低的术语影响。 我们假设遗传DPP4功能丧失将与改善的代谢有关 参数，还具有心力衰竭和相关的生物标志物/成像。我们将在宾夕法尼亚州识别个人 DPP4功能变异及其匹配的控件的医学生物库，并将其招募 表型研究。我们还将招募参与者参加一项试验临床试验，以评估个体的反应 DPP4功能丧失对药理DPP4抑制的杂合子。 候选人拥有一个强大的多学科指导团队，由患者研究专家， 遗传学，内分泌学，心脏病学（晚期心力衰竭），数学建模/生物统计学和 代谢组学/蛋白质组学。候选人将在奖励期间获得必要的技能和专业知识 遗传学的领域，一种基于遗传的临床试验方法，胰岛素的数学建模 敏感性和胰岛素分泌，高级生物统计学和领导能力。这将有助于候选人 实现必要的里程碑，成为一名独立的学术医师科学家 使用遗传学和临床试验方法来回答T2DM和代谢中的问题 风险和相关疗法。