Mechanisms of Junctophilin-2 Misregulation that contribute to right ventricular dysfunction in pulmonary arterial hypertension

Junctophilin-2 失调导致肺动脉高压右心室功能障碍的机制

• 批准号: 10208937
• 负责人: Kurt W Prins
• 金额: $ 14.73万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208937
• 关键词: Affect; Animal Model; Animals; Applications Grants; Attenuated; Basic Science; Calcium; Calcium Channel; Calpain; Cardiac; Cardiac Output; Cardiology; Cardiovascular Diseases; Cell membrane; Cessation of life; Chronic; Clinical; Colchicine; Collaborations; Cytoskeleton; Data; Disease; Doctor of Philosophy; Down-Regulation; Duchenne cardiomyopathy; Echocardiography; Economic Burden; Embryo; Exercise; Exposure to; FDA approved; Failure; Functional disorder; Funding; Future; Goals; Health Care Costs; Heart; Heart failure; Hypertrophic Cardiomyopathy; Hypoxia; Knock-out; Laboratories; Left ventricular structure; Life; Link; Lung; Manuscripts; Mediating; Mediator of activation protein; Mentors; Messenger RNA; Metabolic; Microtubule Depolymerization; Microtubules; Minnesota; Modeling; Molecular; Monocrotaline; Morphology; Mutation; Myocardial dysfunction; Outcome; Pathologic; Pattern; Pharmaceutical Preparations; Phenotype; Physicians; Physiologic intraventricular pressure; Physiology; Play; Proteins; Pulmonary artery structure; Rattus; Regulation; Repression; Research; Research Personnel; Research Project Grants; Research Training; Resistance; Right Ventricular Dysfunction; Right Ventricular Function; Rodent Model; Role; Ryanodine Receptor Calcium Release Channel; Scientist; Severities; Severity of illness; Structure; Survival Analysis; Testing; Training; Training Programs; United States; United States National Institutes of Health; Universities; Ventricular; Walking; Work; career; density; design; exercise capacity; experience; gene repression; heart function; hemodynamics; improved; in vivo; interest; junctophilin; link protein; loss of function; mortality; new therapeutic target; next generation; novel therapeutic intervention; pressure; protein transport; pulmonary arterial hypertension; skills; trafficking; treadmill; voltage

Project Summary The goals of this project are to train Kurt Prins MD, PhD as a physician-scientist in Cardiology and advance the understanding of right ventricular dysfunction in pulmonary arterial hypertension (PAH). Dr. Prins is currently a third year Cardiology fellow in the Physician-Scientist Training Program, a combined research and clinical track dedicated to training the next generation of physician-scientist at the University of Minnesota. Dr. Prins has elected to conduct his research training in the laboratory of Dr. Joseph Metzger, a leader in molecular cardiac physiology who has a long track record of obtaining NIH funding and experience training physician-scientists. Dr. Prins has chosen two experts in pulmonary arterial hypertension research: Drs. Stephen Archer and E. Kenneth Weir to be on his mentoring committee to further guide him in his early career. Dr. Prins’ educational objectives include gaining expertise in cardiac physiology by working in a lab of an established investigator in cardiology and collaborating with an expert in PAH, attending seminars to gain further exposure to outside investigators and build collaborations, and taking courses to prepare for future grant applications. The research project will investigate two distinct mechanisms of junctophilin-2 misregulation that contribute to right ventricular dysfunction in PAH. Dr. Prins authored a manuscript that showed increased microtubule density was associated with junctophilin-2 misregulation resulting in t-tubule disruptions and calcium mishandling in Duchenne cardiomyopathy. Now he will define the role of junctophilin-2 in RV dysfunction in PAH, a disease that he has worked to specialize in clinically. Thus, this proposed training period will allow Dr. Prins to combine his basic science and clinical interests by studying the link between junctophilin-2 misregulation due to improper trafficking on a pathologically remodeled microtubule cytoskeleton and miR-24-mediated repression and RV dysfunction in PAH. The project will determine if misregulation of junctophilin-2 leads to altered t-tubule structure, calcium mishandling, and ultimately RV dysfunction in pulmonary arterial hypertension. Also, it will also test the hypothesis that normalizing junctophilin-2 with colchicine treatment and by inhibiting miR-24 could be novel therapeutic strategies to improve RV function in PAH.

项目摘要 该项目的目标是培养库尔特普林斯医学博士，博士作为一个医生，科学家在心脏病学和推进 了解肺动脉高压（PAH）的右心室功能障碍。普林斯博士目前是第三位 一年的心脏病学研究员在医生科学家培训计划，一个综合的研究和临床轨道，致力于 在明尼苏达大学培养下一代的医学科学家。普林斯医生选择了 约瑟夫·梅茨格博士实验室的研究培训，他是分子心脏生理学的领导者， 获得NIH资助的记录和培训医生科学家的经验。普林斯博士选择了两位专家， 肺动脉高压研究：Stephen Archer和E.肯尼斯·威尔将加入他的指导委员会， 在他早期的职业生涯中，他也有过这样的经历。普林斯博士的教育目标包括通过以下方式获得心脏生理学方面的专业知识： 在心脏病学既定研究者的实验室工作，并与PAH专家合作，参加研讨会 进一步接触外部研究人员，建立合作关系，并参加课程，为未来的赠款做准备 应用.该研究项目将调查两种不同的机制junctophilin-2失调，有助于 PAH患者的右心室功能障碍。普林斯博士撰写的一篇手稿表明，微管密度增加 与嗜连接蛋白-2失调相关，导致Duchenne中的t-小管破坏和钙处理不当 心肌病现在，他将确定嗜连接蛋白-2在PAH的RV功能障碍中的作用， 专攻临床。因此，这一拟议的培训期间将允许博士普林斯联合收割机结合他的基础科学和临床 通过研究由于病理学上的不适当贩运导致的嗜连接蛋白-2失调之间的联系， PAH中微管细胞骨架重塑和miR-24介导的抑制和RV功能障碍。该项目将 确定junctophilin-2的失调是否导致t-小管结构改变，钙处理不当，最终导致RV 肺动脉高压的功能障碍。此外，它还将检验用标准化嗜连接蛋白-2的假设。 秋水仙碱治疗和抑制miR-24可能是改善PAH中RV功能的新治疗策略。