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

项目摘要 该项目的目标是将Kurt Prins医学博士、博士培养为心脏病学的内科科学家，并推动 对肺动脉高压右室功能不全的认识。普林斯博士目前是 年参加医生-科学家培训计划的心脏病学研究员，这是一个致力于 在明尼苏达大学培养下一代内科科学家。普林斯博士选择进行他的 在约瑟夫·梅茨格博士的实验室里进行研究培训，他是分子心脏生理学的领军人物，有很长的研究轨迹 获得国立卫生研究院资助的记录和培训内科科学家的经验。普林斯博士选择了两位专家 肺动脉高压研究：斯蒂芬·阿彻博士和E.Kenneth Weir博士将加入他的指导委员会 进一步指导他的早期职业生涯。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专业知识 在心脏病学知名研究人员的实验室工作，与PAH专家合作，参加研讨会 进一步接触外部调查人员，建立合作关系，并参加课程为未来的拨款做准备 申请。该研究项目将调查两种不同的连接素-2错误调节机制。 右心功能不全的PAH。普林斯博士撰写的一篇手稿显示，微管密度增加 Duchenne患者与连接蛋白-2调控错误相关，导致T-小管破裂和钙处理不当 心肌病。现在他将确定连接素-2在PAH右室功能障碍中的作用，这是他一直致力于研究的疾病 专攻临床。因此，这一拟议的培训期将使普林斯博士能够将他的基础科学和临床结合起来 兴趣通过研究连接蛋白-2错误调节之间的联系，这是由于在病理上不适当的转运 重塑的微管细胞骨架和miR-24介导的PAH抑制和RV功能障碍。该项目将 确定连接蛋白-2的错误调节是否会导致T-小管结构改变、钙处理不当，最终导致右室 肺动脉高压中的功能障碍。此外，它还将检验这样一种假设，即用 秋水仙碱治疗和通过抑制miR-24可能是改善PAH右室功能的新的治疗策略。

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.