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: 10631680
• 负责人: Jessica Rose Wilson
• 金额: $ 5.4万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631680
• 关键词: Adult; Antigens; Area; Award; Biometry; Brain natriuretic peptide; CXCL12 gene; Cardiology; Cardiovascular Diseases; Cardiovascular system; Clinic; Clinical; Clinical Trials; Data; Dipeptidyl Peptidases; Endocrinology; Enrollment; Functional disorder; Genes; Genetic; Glucose; Heart failure; Hospitalization; Human; Human Genetics; Individual; Leadership; Link; Long-Term Effects; Medicine; Mentors; Metabolic; Metabolism; Morbidity - disease rate; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Patients; Pharmacology; Phenotype; Physicians; Pilot Projects; Proteomics; Risk; Scientist; Substance P; Variant; base; biobank; cardiometabolism; cardiovascular effects; cardiovascular risk factor; diabetes mellitus therapy; diabetes risk; glucagon-like peptide 1; imaging biomarker; improved; individual response; inhibitor; insight; insulin secretion; insulin sensitivity; loss of function; mathematical model; metabolomics; mortality; multidisciplinary; patient oriented research; peptide P; recruit; skills

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 and Mayo Clinic 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 in 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 可能是为T2DM疗法和连接T2DM的机制的长期影响提供见解的策略 和心血管风险。二肽基肽酶4（DPP4）抑制剂用于治疗T2DM和 减少可能具有代谢或心血管效应（例如胰类作用）的底物降解 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的好处，DPP4抑制剂也与 心力衰竭住院的风险增加（例如在萨克拉列汀期间），可能与阴性有关 神经肽，CXCL12和物质P.长期数据对DPP4的心血管影响的长期数据 抑制作用仍然有限，因为DPP4抑制剂的最长心血管结局试验仅为三个 年。我们在宾夕法尼亚医学生物库中个人的初步数据表明，基因负担 分析功能变异的罕见丧失，DPP4功能丧失与心脏显着相关 失败。 DPP4功能丧失的表型人将为可能的进一步见解 这种发现的机制和人类DPP4活性降低和抗原的长期影响。 我们假设遗传DPP4功能丧失将与改善的代谢参数有关 而且还具有心力衰竭和相关的生物标志物/成像。我们将确定宾夕法尼亚医学中的个人 DPP4功能变体损失及其匹配的对照和招募 他们进行表型研究。我们还将让参与者参加试验临床试验，以评估 个体杂合子DPP4功能丧失了药物DPP4抑制作用。 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，募集的方法，数学建模 胰岛素敏感性和胰岛素分泌，高级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，成为独立的学术医师科学家 专门研究遗传学和临床试验方法，以回答T2DM和 代谢，心血管风险和相关疗法。