A Pathogenic Role for Natriuretic Peptide Receptor-C in Pulmonary Hypertension and Heart Failure with Preserved Ejection Fraction

钠尿肽受体-C 在肺动脉高压和射血分数保留的心力衰竭中的致病作用

• 批准号: 10301687
• 负责人: Vineet Agrawal
• 金额: $ 15.84万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301687
• 关键词: Advisory Committees; Affect; Agonist; Animal Model; Biogenesis; Biopsy Specimen; Cardiac Myocytes; Cardiovascular system; Catheterization; Cause of Death; Cell Line; Cell model; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Data; Development; Diagnosis; Disease; EFRAC; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Failure; Foundations; Funding; Generations; Genes; Genus Hippocampus; Goals; Heart; Heart failure; High Fat Diet; Hospitalization; Human; Hypertrophy; Impairment; In Vitro; Knock-out; Knockout Mice; Measurement; Mediating; Medicine; Mentors; Mentorship; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Myoblasts; Myocardial; Natriuresis; Natriuretic Peptides; Obesity; Outcome; Pathogenesis; Pathogenicity; Patients; Peptide Receptor; Physicians; Plasmids; Prevention; Principal Investigator; Pulmonary Hypertension; Regulation; Relaxation; Research; Resources; Respiration; Right Ventricular Dysfunction; Right Ventricular Function; Right ventricular structure; Role; Scientist; Signal Pathway; Signal Transduction; Surface; Tamoxifen; Techniques; Testing; Tissues; Training; Training Support; Transgenic Mice; Ventricular; Western Blotting; Work; career; career development; epidemiology study; fatty acid oxidation; improved; improved outcome; in vivo; induced pluripotent stem cell; knock-down; metabolomics; mitochondrial dysfunction; mortality; myocardial biopsy; new therapeutic target; novel; novel therapeutics; obesity treatment; overexpression; patient population; preservation; prevent; protein expression; receptor; receptor expression; skills; therapeutic evaluation; therapeutic target

Project Summary/Abstract: Heart failure with preserved ejection fraction (HFpEF) affects over 3 million people nationwide and carries a 75% 5-year mortality. Unlike other forms of heart failure, there are currently no treatment options for HFpEF that reduce mortality. A common cause of morbidity and mortality in HFpEF is right ventricular (RV) failure, and there are currently no therapies directly targeting RV failure in heart failure. Regardless of the cause, studies have shown that the failing RV undergoes a metabolic shift characterized by decreased utilization of fatty acid oxidation for energy generation and increased mitochondrial dysfunction. While restoring fatty acid oxidation and mitochondrial function are thought to be beneficial, there are currently no therapies that can successfully do so in the failing RV. The goal of the proposal is to support the career development of Dr. Vineet Agrawal by providing him the training, mentorship, and resources to pursue a career in identifying mechanisms by which obesity and metabolic dysfunction fundamentally alter RV metabolism to promote failure, and secondarily identify viable therapies to improve outcomes in a patient population that currently has none. This work is supported by primary mentor, Dr. Anna Hemnes, and a complementary research advisory committee. Dr. Agrawal will leverage their combined mentorship to study the role of a novel therapeutic target, natriuretic peptide clearance receptor NPRC, in the treatment of obesity-induced HFpEF. The central hypothesis of this proposal is that increased NPRC expression in the HFpEF RV results in RV failure through impaired mitochondrial biogenesis and fatty acid oxidation. This central hypothesis will be tested in two specific aims that will test the following hypotheses: (1) that knockdown of NPRC in a model of obesity-induced HFpEF prevents and reverses RV failure by restoring fatty acid oxidation and mitochondrial biogenesis, and (2) NPRC directly inhibits mitochondrial biogenesis and fatty acid oxidation in vitro through cAMP and cGMP-mediated regulation of PGC1α. This proposal will utilize a novel transgenic mouse in which NPRC can inducibly be knocked out to study the role of NPRC in vivo, and CRISPR edited human induced pluripotent stem cells and H9C2 cardiomyocyte-like cells to study the role of NPRC in modulating cardiomyocyte function in vitro. Through the studies proposed to test the hypotheses above, Dr. Agrawal will also accomplish the following career development and training objectives to: (1) master techniques to study mitochondrial function and metabolism of tissue and cells, (2) master techniques to generate and differentiate human induced pluripotent stem cells and cardiomyocytes (hiPSCs), (3) master techniques in gene editing in vitro, and (4) refine professional development and communication skills to achieve goals of academic progress, effective communication, and successful R01 submission.

项目摘要/摘要： 射血分数保留型心力衰竭 (HFpEF) 影响全国超过 300 万人，并导致 与其他形式的心力衰竭不同，HFpEF 的 5 年死亡率为 75%。 降低 HFpEF 发病率和死亡率的常见原因是右心室 (RV) 衰竭，以及 研究显示，无论何种原因，目前尚无直接针对心力衰竭的右心室衰竭的治疗方法。 研究表明，衰竭的 RV 会经历代谢转变，其特征是脂肪酸利用率下降 氧化以产生能量并增加线粒体功能障碍，同时恢复脂肪酸氧化。 线粒体功能被认为是有益的，但目前还没有任何疗法可以成功 在失败的 RV 中这样做 该提案的目标是通过以下方式支持 Vineet Agrawal 博士的职业发展。 为他提供培训、指导和资源，以从事确定机制的职业生涯 肥胖和代谢功能障碍从根本上改变 RV 代谢，从而促进衰竭，其次 找出可行的疗法来改善目前没有疗法的患者群体的治疗效果。 由主要导师 Anna Hemnes 博士和补充研究顾问委员会 Dr. Anna Hemnes 提供支持。 阿格拉瓦尔将利用他们的指导来研究新型治疗靶点利尿钠的作用 肽清除受体 NPRC，治疗肥胖引起的 HFpEF 的核心假设。 建议认为 HFpEF RV 中 NPRC 表达增加会导致 RV 衰竭 线粒体生物合成和脂肪酸氧化这一中心假设将在两个具体目标中得到检验。 这将检验以下假设：(1) 在肥胖诱导的 HFpEF 模型中敲低 NPRC 通过恢复脂肪酸氧化和线粒体生物合成来预防和逆转 RV 衰竭，以及 (2) NPRC 通过 cAMP 和 cGMP 介导直接抑制体外线粒体生物发生和脂肪酸氧化 该提案将利用一种新型转基因小鼠，其中 NPRC 可以被诱导。 敲除研究NPRC在体内的作用，CRISPR编辑人类诱导多能干细胞并 H9C2 心肌细胞样细胞，用于研究 NPRC 在体外调节心肌细胞功能中的作用。 通过为检验上述假设而提出的研究，Agrawal 博士还将实现以下目标 职业发展和培训目标是：（1）掌握研究线粒体功能的技术和 组织和细胞的代谢，（2）掌握人诱导多能细胞的生成和分化技术 干细胞和心肌细胞（hiPSC），（3）掌握体外基因编辑技术，（4）完善 专业发展和沟通技巧，以实现学术进步和有效性的目标 沟通，并成功提交 R01。