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The Calpain/CaMKII/NHE Signaling Pathway in PAH

PAH 中的 Calpain/CaMKII/NHE 信号通路

基本信息

批准号：
9319804
负责人：
John Huetsch
金额：
$ 17.17万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319804
关键词：
Animal Model Apoptosis Attenuated Blood Pressure Blood Vessels Calpain Caspase Cell Proliferation Cell physiology Chronic Cleaved cell Communication Cytoskeletal Modeling Data Data Analyses Development Disease Experimental Designs Family Fostering Functional disorder Future Genetic Goals Grant Growth Human Hypoxia In Vitro Investigation Knockout Mice Lesion Link Lung Measurement Mentors Mentorship Modeling Molecular Morbidity - disease rate Mus Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phosphorylation Physicians Platelet aggregation Prevention Process Protein-Serine-Threonine Kinases Publications Pulmonary Hypertension Research Personnel Rodent Model SU 5416 Scientist Severities Signal Pathway Signal Transduction Smooth Muscle Myocytes Techniques Testing Training Training Programs Transgenic Mice Translating Vascular Proliferation Vascular remodeling Vasodilator Agents base calmodulin-dependent protein kinase II career development cell growth cell motility design gain of function in vitro testing in vivo inhibitor/antagonist innovation insight knock-down laboratory experience link protein loss of function migration mortality new therapeutic target novel novel therapeutics overexpression pressure prevent pulmonary arterial hypertension response response to injury skills therapy design vasoconstriction

项目摘要

PROJECT SUMMARY / ABSTRACT The objectives of this K08 proposal are two-fold: 1) to provide the candidate with the essential scientific and professional skills to become an independent physician-scientist focused on the molecular and cellular pathogenesis of pulmonary hypertension, and 2) to investigate the mechanisms underlying pathologic pulmonary arterial smooth muscle cell (PASMC) proliferation and migration in pulmonary arterial hypertension (PAH). Dr. Huetsch and his mentor, Dr. Larissa Shimoda, have designed a training plan that combines laboratory experience, coursework, and professional mentorship to foster expertise in experimental design and techniques, data analysis, and scientific communication. This training will occur through the investigation of a novel signaling pathway underlying PASMC dysfunction and pulmonary vascular remodeling in PAH, a disease which continues to cause significant morbidity and mortality owing to the lack of therapies designed to reverse vascular remodeling. Based on our preliminary data, we hypothesize that, in PAH, increased calpain activity in PASMCs leads to activation of Ca2+/calmodulin dependent protein kinase II (CaMKII), which then induces increased activity of the Na+/H+ exchanger (NHE), resulting in pathologically elevated PASMC proliferation and migration and pulmonary vascular remodeling. Using PASMCs isolated from PAH patients as well as the Sugen/hypoxia rodent model of PAH, we plan to investigate this hypothesis through three aims: 1) to determine whether calpains are necessary for vascular remodeling in PAH, 2) to determine whether CaMKII is necessary for vascular remodeling in PAH, and 3) to determine whether NHE is necessary for vascular remodeling in PAH. We plan to utilize genetic, molecular, and pharmacologic techniques to induce gain-of- function and loss-of-function of each component of this pathway with subsequent measurements of 1) activity of downstream components of the pathway, 2) PASMC proliferation and migration in vitro, and 3) prevention and/or reversal of pulmonary vascular remodeling in vivo. Accomplishment of these aims will provide a rigorous training program for Dr. Huetsch and uncover novel mechanisms underlying pathologic PASMC function in PAH which could hopefully be translated into new therapeutic targets.

项目总结/摘要这个K 08提案的目标是双重的：1）为候选人提供必要的科学和专业技能，成为一个独立的医生，科学家专注于分子和细胞肺动脉高压的发病机制，2）探讨病理机制，肺动脉高压时肺动脉平滑肌细胞增殖和迁移（PAH）。Huetsch博士和他的导师Larissa Shimoda博士设计了一个培训计划，实验室经验，课程和专业指导，以培养实验设计和技术、数据分析和科学交流。这项培训将通过调查一个 PAH患者PASMC功能障碍和肺血管重构的新信号通路由于缺乏旨在逆转这种疾病的治疗方法，血管重塑根据我们的初步数据，我们假设，在PAH中， PASMCs导致Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）的激活，然后诱导 Na+/H+交换器（NHE）活性增加，导致PASMC增殖病理性升高和肺血管重塑。使用从PAH患者中分离的PASMCs以及 Sugen/缺氧的PAH啮齿动物模型，我们计划通过三个目的来研究这一假设：1）确定钙蛋白酶是否是PAH血管重塑所必需的，2）确定CaMKII是否是 PAH中血管重塑所必需的，以及3）确定NHE是否是血管重塑所必需的。 PAH中的重塑。我们计划利用遗传学、分子学和药理学技术来诱导获得- 该途径的每个组分的功能和功能丧失，随后测量1）活性 2）体外PASMC增殖和迁移，以及3）预防和/或逆转体内肺血管重塑。实现这些目标将提供一个 Huetsch博士的严格培训计划，并揭示病理性PASMC的新机制在PAH中发挥作用，有望转化为新的治疗靶点。