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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

基本信息

批准号：
10436188
负责人：
Kurt W Prins
金额：
$ 12.33万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/10436188
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 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 antagonist 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 right ventricular failure skills trafficking treadmill voltage

项目摘要

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。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure.

右心室衰竭的多组学和多物种分析。

DOI：
10.1101/2023.02.08.527661
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Mendelson,JennaB;Sternbach,JacobD;Doyle,MichelleJ;Mills,Lauren;Hartweck,LynnM;Tollison,Walt;Carney,JohnP;Lahti,MatthewT;Bianco,RichardW;Kalra,Rajat;Kazmirczak,Felipe;Hindmarch,Charles;Archer,StephenL;Prins,KurtW;Martin
通讯作者：
Martin

Survival in pulmonary hypertension due to chronic lung disease: Influence of low diffusion capacity of the lungs for carbon monoxide.

DOI：
10.1016/j.healun.2018.09.011
发表时间：
2019-03
期刊：
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
影响因子：
0
作者：
Rose L;Prins KW;Archer SL;Pritzker M;Weir EK;Misialek JR;Thenappan T
通讯作者：
Thenappan T

An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats.

DOI：
10.3389/fphys.2022.966454
发表时间：
2022
期刊：
Frontiers in physiology
影响因子：
4
作者：
通讯作者：

Association of right ventricular dysfunction and pulmonary hypertension with adverse 30-day outcomes in COVID-19 patients.

右心室功能障碍和肺动脉高压与190例患者的30天结局的关联。

DOI：
10.1177/20458940211007040
发表时间：
2021-04
期刊：
Pulmonary circulation
影响因子：
2.6
作者：
Wats K;Rodriguez D;Prins KW;Sadiq A;Fogel J;Goldberger M;Moskovits M;Tootkaboni MP;Shani J;Jacob J
通讯作者：
Jacob J

ApoM Activates Autophagy and Suppresses Lyosomal Lethargy to Combat Doxorubicin Cardiomyopathy.

ApoM 激活自噬并抑制溶酶体嗜睡，以对抗阿霉素心肌病。