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.

项目总结