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）

• 批准号: 10454568
• 负责人: Jessica Rose Wilson
• 金额: $ 9.41万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 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/10454568
• 关键词: Adipocytes; Adult; Age; Agonist; Animal Model; Antigens; Area; Atherosclerosis; Award; Biological Markers; Biometry; Body mass index; 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; Grant; 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 effects; 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