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Mechanisms and treatment of right ventricular sarcomere dysfunction in scleroderma-associated pulmonary arterial hypertension

硬皮病相关肺动脉高压右心室肌节功能障碍的机制及治疗

基本信息

批准号：
10593922
负责人：
Steven Hsu
金额：
$ 17.71万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593922
关键词：
Activities of Daily Living Advisory Committees Area Autoimmune Diseases Award Basic Science Biopsy Blood Vessels Calcium Cardiac Cardiac Myocytes Cardiology Chemicals Clinical Clinical Data Clinical Research Data Dedications Defect Dependence Depressed mood Disease Disease Progression Doctor of Medicine Failure Follow-Up Studies Functional disorder Funding Goals Human Human Rights Incubated K-Series Research Career Programs Levosimendan Lung Measurement Measures Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Methods Microvascular Dysfunction Molecular Muscle Cells Myocardium National Heart, Lung, and Blood Institute Nature Onset of illness Organ Outcome Pathologic Pathology Patient Care Patients Peptide Fragments Pharmaceutical Preparations Pharmacotherapy Phosphorylation Physicians Physiologic intraventricular pressure Physiology Play Post-Translational Protein Processing Process Protein Analysis Proteins Publications Pulmonary Hypertension Records Research Research Personnel Research Proposals Rest Right Ventricular Dysfunction Right Ventricular Function Role Sarcomeres Scientist Scleroderma Skin Stress Subgroup Testing Therapeutic Training Translational Research Treatment Efficacy Troponin Troponin I United States National Institutes of Health Universities Vasodilator Agents Ventricular Work career career development cohort efficacy evaluation efficacy testing functional restoration hemodynamics hypertension control improved in vivo innovation mortality myosin-binding protein C nitroxyl novel therapeutics pharmacologic pressure primary pulmonary hypertension professor prospective pulmonary arterial hypertension response right ventricular failure skill acquisition skills translational scientist

项目摘要

Steven Hsu, M.D. is an Assistant Professor in the Division of Cardiology at Johns Hopkins University. Dr. Hsu seeks an NIH Mentored Patient-Oriented Research Career Development Award in order to obtain the expertise and skills necessary to launch a translational research career focused on human right ventricular (RV) failure. Dr. Hsu has elected to work with primary mentor Dr. David Kass, a pioneer in cardiac physiology and molecular pathobiology, and co-mentor Dr. Paul Hassoun, a thought leader in pulmonary hypertension. Both occupy complementary areas of research expertise, work together seamlessly, and boast long track records of successful funding and training of physician-scientists. A complementary group of collaborators will assist in the research and form an advisory committee as well. Dr. Hsu will leverage their combined mentorship to study the molecular underpinnings of RV sarcomere dysfunction in human scleroderma-associated pulmonary arterial hypertension (PAH). The specific aims of his research proposal are to: (1) identify the alterations in sarcomere proteins troponin I and myosin-binding protein C that underlie the in vivo RV dysfunction of human scleroderma-associated PAH; and (2) determine which RV-directed pharmacotherapies would best restore function in failing RV sarcomeres isolated from these same subjects. Dr. Hsu's career development training objectives during this award period are to develop proficiency in clinical studies, master invasive RV pressure- volume hemodynamics, broaden his translational basic science skillset, and prepare for independent investigator funding. These will enable Dr. Hsu's long-term goal of developing a career dedicated to the translational investigation of human RV heart failure. PAH is a deadly disease resulting from a pathologic increase in pulmonary vascular load. Although pulmonary vasodilator therapies have helped many, the scleroderma-associated PAH subgroup lags far behind its PAH counterparts in terms of functional capacity and survival. Dr. Hsu has first authored two high impact publications showing that failure of RV adaptation in scleroderma-associated PAH is the likely culprit. Scleroderma-associated PAH patients suffer disproportionate RV contractile dysfunction when compared to idiopathic PAH and normal controls, both at the in vivo RV chamber level and the ex vivo RV sarcomere level. Understanding and treating this RV dysfunction would meet a major unmet need in the care of patients with PAH. Preliminary work thus far points towards explanatory molecular alterations in the key sarcomere proteins troponin I and myosin-binding protein C. The proposed research will test the centrality of these two sarcomere proteins to the chamber and cellular RV dysfunction of human scleroderma-associated PAH, while also determining the efficacy of therapeutics directed against the failing RV sarcomere. In doing so, this work seeks to clarify the molecular mechanisms of RV failure in scleroderma-associated PAH, while also innovating the treatment paradigm for the field of PAH.

Steven Hsu，医学博士是约翰霍普金斯大学心脏病学系的助理教授。许倬寻求NIH指导的以患者为导向的研究职业发展奖，以获得专业知识和必要的技能，以启动一个转化研究的职业生涯，重点是人类右心室（RV）失败。博士徐已经选择与主要导师大卫卡斯博士，心脏生理学的先驱，分子病理生物学和共同导师保罗·哈桑博士，肺动脉高压的思想领袖。两占据研究专业知识的互补领域，无缝合作，并拥有长期的跟踪记录，成功地资助和培训了医生和科学家。一个补充的合作者小组将协助并成立咨询委员会。徐博士将利用他们的联合导师学习人硬皮病相关性肺动脉高压中RV肌节功能障碍的分子基础动脉高血压（PAH）。他的研究计划的具体目标是：（1）确定肌节蛋白肌钙蛋白I和肌球蛋白结合蛋白C是人体RV功能障碍的基础硬皮病相关PAH;（2）确定哪种RV导向药物治疗最能恢复功能衰竭的RV肌节分离自这些相同的主题。徐博士的职业发展培训在此奖项期间的目标是发展熟练的临床研究，掌握有创RV压力- 体积血流动力学，拓宽他的翻译基础科学技能，并准备独立调查资金。这将使许博士的长期目标，发展事业，致力于人RV心力衰竭的转化研究。PAH是一种致命的疾病，肺血管负荷增加。虽然肺血管扩张剂治疗对许多人有帮助，在功能能力方面，硬皮病相关PAH亚组远远落后于PAH亚组，生存徐博士首先撰写了两篇影响力很大的出版物，表明RV适应失败，硬皮病相关PAH可能是罪魁祸首。硬皮病相关PAH患者遭受不成比例的与特发性PAH和正常对照相比，在体内RV时，RV收缩功能障碍室水平和离体RV肌节水平。了解和治疗这种RV功能障碍将满足 PAH患者护理中的一个主要未满足需求。迄今为止的初步工作表明，关键肌节蛋白肌钙蛋白I和肌球蛋白结合蛋白C的分子改变。拟议研究将测试这两种肌节蛋白对心室的中心作用和细胞RV功能障碍，人硬皮病相关PAH，同时也确定针对右心室肌节衰竭在这样做的过程中，这项工作试图澄清RV失败的分子机制，硬皮病相关PAH，同时也创新了PAH领域的治疗模式。