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

• 批准号: 9904326
• 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
• 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/9904326
• 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; Defect; Dependence; Depressed mood; Disease; Disease Progression; Doctor of Medicine; Failure; Follow-Up Studies; Functional disorder; Funding; Goals; Heart failure; Human; Human Rights; Incubated; Investigation; 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; Pharmacology; 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 testing; functional restoration; hemodynamics; improved; in vivo; innovation; mortality; myosin-binding protein C; nitroxyl; novel therapeutics; pressure; primary pulmonary hypertension; professor; prospective; pulmonary arterial hypertension; response; skills; translational scientist

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.

史蒂文·许，医学博士，约翰·霍普金斯大学心内科助理教授。许博士 寻求NIH以患者为导向的导师研究职业发展奖，以获得专业知识 以及启动专注于人类右室(RV)衰竭的翻译研究生涯所需的技能。 徐博士选择与心脏生理学和心脏生理学的先驱大卫·卡斯博士合作 分子病理生物学，以及共同导师保罗·哈桑博士，他是肺动脉高压的思想领袖。两者都有 占据研究专业知识的互补领域，无缝合作，并拥有长期的 成功资助和培训内科科学家。一个互为补充的协作者小组将协助 研究并成立了一个咨询委员会。徐博士将利用他们的联合导师来研究 人硬皮病相关性肺RV肌节功能障碍的分子基础 动脉高血压(PAH)。他的研究提案的具体目标是：(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 硬皮病相关的PAH；以及(2)确定哪些RV导向的药物疗法将最好地恢复 从这些相同的受试者中分离的RV肌节在衰竭中的作用。许博士的职业发展培训 获奖期间的目标是熟练掌握临床研究，掌握有创房室压力- 体积血流动力学，拓宽他的翻译基础科学技能，并为独立做准备 调查人员的资助。这些都将使许博士的长期目标得以实现，即发展致力于 人类RV心力衰竭的翻译研究。PAH是一种致命的疾病，由一种病理性的 肺血管负荷增加。尽管肺血管扩张剂疗法帮助了许多人，但 与硬皮病相关的PAH亚组在功能能力和 生死存亡。许博士首先撰写了两篇影响较大的出版物，表明房车适应在 硬皮病相关的多环芳烃可能是罪魁祸首。硬皮病相关的PAH患者遭受不成比例的 与特发性PAH和正常对照相比，在活体RV中的RV收缩功能障碍 房室水平和体外RV肌节水平。了解和治疗这种RV功能障碍将满足 帕金森病患者护理中未得到满足的主要需求。到目前为止的初步工作指向解释 肌节关键蛋白肌钙蛋白I和肌球蛋白结合蛋白C的分子变化 研究将测试这两种肌节蛋白对房室和细胞RV功能障碍的中心性。 人类硬皮病相关的PAH，同时也确定针对硬皮病相关PAH的治疗方法的疗效 房车肌节出现故障。通过这样做，这项工作试图澄清RV故障的分子机制 与硬皮病相关的多环芳烃，同时也创新了多环芳烃领域的治疗范例。