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

心肌可溶性鸟苷酸环化酶信号传导对右心室功能障碍的治疗潜力

• 批准号: 9325064
• 负责人: Emily J Tsai
• 金额: $ 8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325064
• 关键词: Acute; Adrenergic Agents; Adrenergic beta-Antagonists; Affect; Angiotensin Receptor; Animal Model; Animals; Award; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiology; Chronic; Clinical; Clinical Trials; Coupling; Cyclic GMP; Data; Disease; Echocardiography; Foundations; Functional disorder; Funding; Future; Goals; Guanosine Monophosphate; Guidelines; Heart; Heart Transplantation; Heart failure; Histology; Hypertrophy; Innovative Therapy; Knowledge; Left Ventricular Ejection Fraction; Left Ventricular Remodeling; Left ventricular structure; Lisinopril; Lung; Measures; Mediating; Medical; Medicine; Mentors; Methods; Metoprolol; Modeling; Molecular; Mus; Muscle relaxation phase; Myocardial; Neprilysin; Outcome; Pathologic; Patients; Periodicity; Pharmaceutical Preparations; Physicians; Physiological; Program Research Project Grants; Pulmonary artery structure; Regulation; Renin-Angiotensin-Aldosterone System; Research; Research Project Grants; Right Ventricular Dysfunction; Right ventricular structure; Scientist; Second Messenger Systems; Signal Pathway; Signal Transduction; Soluble Guanylate Cyclase; Stress; Surgeon; Therapeutic; Therapeutic Uses; Treatment Failure; Universities; Vascular Smooth Muscle; Vasodilator Agents; Ventricular Dysfunction; Ventricular Remodeling; biological adaptation to stress; career; clinical care; clinically relevant; college; constriction; drug development; exercise capacity; experience; experimental study; improved; improved functioning; in vivo; inhibitor/antagonist; insight; mouse model; new therapeutic target; novel; novel strategies; pressure; prevent; professor; pulmonary arterial hypertension; response; targeted treatment; valsartan

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.

该提案描述了一个为期2年的研究项目，将有助于推动指导临床科学家博士。 艾米丽蔡（K 08获奖者）在开发她的第一个研究项目时实现完全的科学独立 资助计划提案（R 01）。PI的长期职业目标是获得原始洞察力， 心力衰竭的病理生理学，以确定药物开发的新靶点，并最终使 创新疗法到临床护理。现在是哥伦比亚大学医学院的助理教授， 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 在不久的将来为竞争性R 01提案奠定基础。因此，这个为期两年的R 03研究项目概述了 这些实验将产生初步数据，并建立对R 01提案至关重要的相关动物模型。 深受她的临床经验，作为一个先进的心脏衰竭和移植心脏病学， PI旨在阐明右心室功能障碍（RVD）的分子病理生理学。RVD是 心力衰竭（HF）预后不良的最强预测因子，与左心室射血分数无关。然而 RVD的病理生物学仍然知之甚少，并且不存在RVD特异性的药物治疗。的PI 已经制定了一项研究策略，以阐明心肌可溶性鸟苷酸 环化酶/环磷酸鸟苷（sGC/cGMP）信号转导，并提供支持的机制数据 增强RVD HF患者sGC/cGMP信号传导的治疗潜力。优化平移 她的研究的重要性，PI建议在体内研究，模仿指南指导的药物治疗 （GDMT）HF。拟议研究计划的主要目标是：1）定义室间差异， sGC/cGMP刺激对心脏功能和重塑的影响;和2）确定GDMT对心脏功能和重塑的影响。 病理性重塑心脏中的心肌sGC/cGMP信号传导。R 03的研究结果如下： 预计将提供新的见解之间的差异和相似性的右心室和左心室， 他们的压力超负荷应激反应此外，研究结果将提供证据， 增强RVD HF中sGC/cGMP信号传导的方法。到R 03奖励期结束时，PI将恢复正常 准备开始作为一个独立的，R 01资助的临床科学家的职业生涯，专注于了解 HF中RVD的分子病理生理学，并开发预防和治疗它的新策略。