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

项目摘要/摘要： 射血分数保留的心力衰竭(HFpEF)影响着全国300多万人，并携带着 75%的5年死亡率。与其他形式的心力衰竭不同，目前还没有针对HFpEF的治疗选择 这会降低死亡率。HFpEF发病和死亡的常见原因是右室(RV)衰竭，以及 目前还没有直接针对心力衰竭的RV衰竭的治疗方法。不管是什么原因，研究 已经表明，衰竭的RV经历了以脂肪酸利用减少为特征的代谢转变 氧化产生能量，增加线粒体功能障碍。在恢复脂肪酸氧化的同时 和线粒体功能被认为是有益的，目前还没有治疗方法可以成功 在故障的房车中这样做。该提案的目标是通过以下方式支持维尼特·阿格拉瓦尔博士的职业发展 为他提供培训、指导和资源，使他能够在职业生涯中确定 肥胖和代谢障碍从根本上改变了RV的代谢，从而促进了衰竭，继而 确定可行的治疗方法，以改善目前没有的患者群体的结果。这项工作是 由主要导师安娜·海姆尼斯博士和一个补充研究咨询委员会提供支持。Dr。 Agrawal将利用他们的联合指导来研究一种新的治疗靶点--钠尿剂的作用 肽清除受体NPRC在肥胖性高脂血症治疗中的作用这一点的中心假设是 建议认为，在HFpEF RV中NPRC表达增加会通过受损导致RV衰竭 线粒体生物发生与脂肪酸氧化。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模型中敲除NPRC 通过恢复脂肪酸氧化和线粒体生物发生来预防和逆转RV衰竭，以及(2)NPRC 在体外通过cAMP和cGMP直接抑制线粒体生物发生和脂肪酸氧化 Pgc1α的调控。这项提议将利用一种新型的转基因小鼠，在这种小鼠中，NPRC可以被诱导 敲除以研究NPRC在体内的作用，CRISPR编辑了人类诱导多能干细胞和 H9C2心肌细胞样细胞，研究NPRC在体外对心肌细胞功能的调节作用。 通过为检验上述假设而提出的研究，阿格拉瓦尔博士还将完成以下工作 职业发展和培训目标：(1)掌握研究线粒体功能和 组织和细胞的新陈代谢，(2)掌握产生和分化人类诱导多能性的技术 干细胞和心肌细胞(HiPSCs)，(3)掌握体外基因编辑技术，(4)提纯 专业发展和沟通能力，实现学业进步的目标，有效 沟通，并成功提交R01。

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.