Therapeutic Potential of Myocardial Soluble Guanylyl Cyclase Signaling in Right Ventricular Dysfunction

该提案描述了一个为期两年的研究项目，该项目将有助于推动指导临床医生-科学家Dr。 蔡慧卿(K08奖获得者)在开发她的第一个研究项目时走向完全的科学独立 资助计划建议书(R01)。PI的长期职业目标是在 心力衰竭的病理生理学，确定药物开发的新靶点，并最终带来 临床护理的创新疗法。现任哥伦比亚大学医学院医学助理教授 医生和外科医生，申请人正在积极扩大她的研究范围，以建立 为在不久的将来提出具有竞争力的R01提案奠定基础。因此，这个为期两年的R03研究项目概述了 将产生初步数据并建立对R01提案至关重要的相关动物模型的实验。 深受她作为一名晚期心力衰竭和移植心脏科医生的临床经验的影响， PI旨在阐明右心功能不全(RVD)的分子病理生理学。差饷物业估价署是 心力衰竭(HF)预后不良的最强预测指标，与左心室射血分数无关。还没有 RVD的病理生物学机制仍然知之甚少，针对RVD的药物治疗尚不存在。《少年派》 已经制定了一项研究策略来阐明心肌中可溶性鸟苷的室间差异 环化酶/环化鸟苷一磷酸(sGC/cGMP)信号转导，并提供机械性数据支持 增强sGC/cGMP信号通路对RVD心力衰竭的治疗潜力。要优化翻译版本， 她的研究的意义，PI提出了模仿指南指导的药物治疗的体内研究 (GDMT)。拟议的研究计划的主要目标是：1)确定心脏的室间差异 SGC/cGMP刺激对心功能和重构的影响；2)确定GDMT对心功能和重构的影响。 病理重塑心脏中的心肌sGC/cGMP信号转导。这款R03的研究成果是 预计将提供新的见解，以了解右和左心室之间的差异和相似之处 关于他们的压力过载应激反应。此外，研究结果将提供最佳的证据 S等人在RVD心衰时增强sGC/cGMP信号转导途径的研究。到R03颁奖期结束时，PI将会很好 准备作为一名独立的、由R01资助的临床医生科学家开始职业生涯，专注于了解 心衰RVD的分子病理生理学及新的防治策略。

This proposal describes a 2-year research project that will help propel mentored clinician-scientist Dr. Emily Tsai (a K08 awardee) towards full scientific independence as she develops her first Research Project Grant Program proposal (R01). The PI's long-term career goals are to gain original insight in the pathophysiology of heart failure, to identify novel targets for drug development, and to ultimately bring innovative therapies to clinical care. Now an Assistant Professor of Medicine at Columbia University College of Physicians and Surgeons, the applicant is actively expanding the scope of her research so as to build the foundation for a competitive R01 proposal in the near future. Hence, this 2-year R03 research project outlines experiments that will generate preliminary data and establish relevant animal models vital to the R01 proposal. Profoundly influenced by her clinical experience as an advanced heart failure and transplant cardiology, the PI aims to elucidate the molecular pathophysiology of right ventricular dysfunction (RVD). RVD is the strongest predictor of poor outcomes in heart failure (HF), independent of left ventricular ejection fraction. Yet the pathobiology of RVD remains poorly understood and RVD-specific medical therapy does not exist. The PI has formulated a research strategy to elucidate interventricular differences in myocardial soluble guanylyl cyclase/cyclic guanosine monophosphate (sGC/cGMP) signaling and to provide mechanistic data supporting the therapeutic potential of enhancing sGC/cGMP signaling in HF with RVD. To optimize the translational significance of her studies, the PI proposes in vivo studies that mimic guideline directed medical therapy (GDMT) of HF. The primary goals of the proposed research plan are to: 1) define interventricular differences in sGC/cGMP stimulation on cardiac function and remodeling; and 2) determine the effect of GDMT on myocardial sGC/cGMP signaling in the pathologically remodeled heart. Research findings of this R03 are expected to provide new insights into the differences and similarities between the right and left ventricles with regards to their pressure-overload stress response. Moreover, study results will offer evidence of optimal way(s) to enhance sGC/cGMP signaling in RVD HF. By the end of the R03 award period, the PI will be well poised to launch a career as an independent, R01-funded clinician scientist, focused on understanding the molecular pathophysiology of RVD in HF and developing novel strategies for preventing and treating it.