A Pathogenic Role for the Natriuretic Peptide Clearance Receptor in Heart Failure with Preserved Ejection Fraction.

钠尿肽清除受体在射血分数保留的心力衰竭中的致病作用。

• 批准号: 10589324
• 负责人: Vineet Agrawal
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-03-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589324
• 关键词: Adipose tissue; Advisory Committees; Affect; Animal Model; Biogenesis; Biopsy Specimen; Cardiac; Cardiac Myocytes; Cardiac Output; Cause of Death; Cells; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Data; Development; Disease; EFRAC; Failure; Foundations; Funding; Generations; Genes; Genus Hippocampus; Goals; Heart; Heart Diseases; Heart failure; Hospitalization; Human; Hypertrophy; Impairment; In Vitro; Knock-out; Knockout Mice; Ligands; Measurement; Measures; Mediating; Mentors; Mentorship; Metabolic; Metabolic dysfunction; Metabolism; Methods; Mitochondria; Modeling; Morbidity - disease rate; Myocardial; Natriuresis; Natriuretic Peptides; Obesity; Outcome; PGC1a Regulation Pathway; Pathogenesis; Pathogenicity; Pathway interactions; Physicians; Principal Investigator; Regulation; Relaxation; Research; Resources; Respiration; Reverse Transcriptase Polymerase Chain Reaction; Right Ventricular Dysfunction; Right Ventricular Function; Role; Scientist; Signal Transduction; Structure; Surface; Techniques; Testing; Tissues; Training; Training Support; Transgenic Mice; Transgenic Organisms; Ventricular; Veterans; Work; career; career development; exercise capacity; fatty acid oxidation; heart metabolism; 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; pharmacologic; preservation; prevent; protein expression; receptor; right ventricular failure; skills; therapeutic evaluation; therapeutic target

PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) affects almost 2.5% of all US Veterans, and it contributes to nearly 1 in 14 deaths in Veterans. 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 mentors, Drs. Julie Bastarache and 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 PGC1a. 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 VA Merit submission.

项目概要 射血分数保留的心力衰竭 (HFpEF) 影响着近 2.5% 的美国退伍军人，并且 退伍军人死亡人数中有近四分之一是由该疾病造成的。与其他形式的心力衰竭不同，目前尚无 降低死亡率的 HFpEF 治疗方案。 HFpEF 发病和死亡的常见原因是 右心室（RV）衰竭，目前没有直接针对心力衰竭中的 RV 衰竭的治疗方法。 无论原因如何，研究表明，衰竭的 RV 会经历代谢转变，其特征是 脂肪酸氧化用于能量产生的利用减少，线粒体功能障碍增加。 虽然恢复脂肪酸氧化和线粒体功能被认为是有益的，但目前 没有任何疗法可以成功地治疗失败的 RV。该提案的目标是支持职业生涯 通过为 Vineet Agrawal 博士提供职业发展所需的培训、指导和资源来帮助他发展 确定肥胖和代谢功能障碍从根本上改变 RV 代谢的机制 促进失败，其次确定可行的疗法以改善患者群体的结果 目前没有。这项工作得到了主要导师 Drs 的支持。朱莉·巴斯塔拉奇和安娜·赫姆内斯，以及 一个补充性的研究咨询委员会。阿格拉瓦尔博士将利用他们的联合指导来学习 新的治疗靶点——利尿钠肽清除受体 NPRC——在肥胖治疗中的作用 诱发 HFpEF。该提案的中心假设是 HFpEF RV 中 NPRC 表达增加 通过线粒体生物发生和脂肪酸氧化受损导致 RV 衰竭。这个中心假设 将在两个具体目标中进行测试，这将测试以下假设：（1）在 肥胖引起的 HFpEF 模型通过恢复脂肪酸氧化来预防和逆转 RV 衰竭 (2) NPRC 直接抑制线粒体生物发生和脂肪酸氧化 体外通过 cAMP 和 cGMP 介导的 PGC1a 调节。该提案将利用一种新型转基因 可以诱导敲除 NPRC 的小鼠，以研究 NPRC 在体内的作用，并进行 CRISPR 编辑 人诱导多能干细胞和H9C2心肌细胞样细胞研究NPRC在 体外调节心肌细胞功能。通过为检验上述假设而提出的研究，博士。 阿格拉瓦尔还将完成以下职业发展和培训目标：（1）掌握 研究线粒体功能和组织细胞代谢的技术，（2）掌握研究线粒体功能和组织细胞代谢的技术 生成并分化人类诱导多能干细胞和心肌细胞 (hiPSC)，(3) master 体外基因编辑技术，以及（4）完善专业发展和沟通技巧 实现学术进步、有效沟通和成功提交 VA 成绩的目标。