Role and regulation of vascular permeability in pulmonary fibrosis

血管通透性在肺纤维化中的作用和调节

基本信息

批准号：
9756465
负责人：
Rachel S Knipe
金额：
$ 17.28万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2018-08-05 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756465
关键词：
Actins Advisory Committees Albumins Alveolar Animal Model Attenuated Biology Bleomycin Blood Vessels Cellular biology Chronic Cicatrix Coagulation Process Critical Care Cytoskeleton Data Development Dextrans Disease Disease Progression Dose Dyspnea Endothelial Cells Endothelium Engineering Environment Epithelial Cells Epithelium Extravasation Fibroblasts Fibrosis Flow Cytometry General Hospitals Genetic Goals Hypoxemia In Vitro Injury Label Lead Lipids Lung Lung Transplantation Lung diseases Massachusetts Mediating Medicine Mentors Mentorship Modeling Molecular Biology Molecular Chaperones Mus Pathogenesis Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacology Physicians Physiological Plasma Plasma Proteins Positioning Attribute Proteins Pulmonary Fibrosis ROCK1 gene Records Regulation Reporting Research Respiratory Failure Rho-associated kinase Role Scientist Seeds Signal Transduction Stimulus Stress Fibers System Therapeutic Thrombin Time Tissue Engineering Tissues Training Training Activity Translational Research Treatment Efficacy Universities Vascular Permeabilities Work Wound Healing career cell injury design drug development edg-1 Protein effective therapy experience experimental study fibrogenesis human model idiopathic pulmonary fibrosis indium-bleomycin instructor lung injury medical schools mortality mouse model new therapeutic target novel novel therapeutics overexpression prevent pulmonary vascular permeability repaired response response to injury sphingosine 1-phosphate systems research three dimensional cell culture translational research program

项目摘要

Project Summary Candidate: Rachel Knipe, MD is a physician in the Division of Pulmonary and Critical Care at Massachusetts General Hospital (MGH) and an Instructor of Medicine at Harvard Medical School (HMS). She has developed expertise in cell and molecular biology and murine modeling of pulmonary fibrosis, focusing on the role of ROCK, S1P1 and the actin cytoskeleton in fibrogenesis. This K08 application aims to understand the role of vascular permeability in the development of pulmonary fibrosis, studying two opposing regulators of permeability, ROCK and S1P1. Her short-term goals are to obtain training in endothelial biology, animal modeling of human lung disease, micro-engineered culture systems, and translational research. Her long term goal is to lead a translational research program on vascular permeability and pulmonary fibrosis. The experiments, training, and mentoring plan outlined in this proposal will successfully position Dr. Knipe for her first R01 and an independent career as a physician-scientist. Mentorship, Training Activities and Environment: Dr. Knipe will perform the work outlined in this proposal in the Division of Pulmonary and Critical Care Medicine under the mentorship of Drs. Benjamin Medoff and Andrew Luster. Drs. Medoff and Luster both have extensive experience in mouse modeling of lung disease and translational research and excellent records of mentoring. Drs. James Liao, Timothy Hla, Christopher Chen and Barry Shea will serve on Dr. Knipe's advisory committee and provide expertise in ROCK and S1P1 signaling, mouse modeling of lung disease, cellular biology utilizing advanced micro-engineered culture systems and translational research. Dr. Knipe will complete courses in endothelial biology, mouse modeling of human lung disease, tissue engineering, and translational research through Harvard Medical School and Harvard University. Research: Idiopathic Pulmonary Fibrosis (IPF) is a progressive scarring lung disease that very often leads to respiratory failure. There remains a large unmet need for effective therapies. IPF is thought to be driven by dysfunctional wound healing responses to repetitive tissue injury. Increased vascular permeability is a cardinal wound healing response, which in the lung allows plasma proteins to leak from the pulmonary vasculature into the airspaces. Increased permeability has been shown in the lungs of IPF patients, and predicts mortality. We propose that restoring endothelial barrier function after lung injury, either by inhibiting endothelial cell ROCK activation or augmenting endothelial cell S1P1 activation, could provide a novel and specific therapeutic strategy to attenuate the development of pulmonary fibrosis.

项目概要候选人：雷切尔·奈普 (Rachel Knipe)，医学博士，肺科和重症监护科的一名医生马萨诸塞州总医院 (MGH) 和哈佛医学院医学讲师学校（HMS）。她在细胞和分子生物学以及小鼠建模方面积累了丰富的专业知识肺纤维化的研究，重点关注 ROCK、S1P1 和肌动蛋白细胞骨架在肺纤维化中的作用纤维发生。此 K08 应用旨在了解血管通透性在肺纤维化的发展，研究两种相反的渗透性调节因子，ROCK 和S1P1。她的短期目标是获得内皮生物学、动物建模方面的培训人类肺部疾病、微工程培养系统和转化研究。她的长学期目标是领导一项关于血管通透性和肺功能的转化研究项目纤维化。本提案中概述的实验、培训和指导计划将成功为 Knipe 博士定位她的第一个 R01 和作为一名医师科学家的独立职业生涯。指导、培训活动和环境：Knipe 博士将执行中概述的工作这项提案是在肺科和重症医学科的指导下提出的博士。本杰明·梅多夫和安德鲁·卢斯特。博士。 Medoff 和 Lustre 都拥有广泛的在小鼠肺部疾病建模和转化研究方面拥有丰富的经验和优秀的记录的指导。博士。 James Liao、Timothy Hla、Christopher Chen 和 Barry Shea 将在 Dr. Knipe 的顾问委员会提供 ROCK 和 S1P1 信号传导、鼠标方面的专业知识利用先进的微工程培养系统进行肺部疾病、细胞生物学建模和转化研究。 Knipe 博士将完成内皮生物学、小鼠课程人类肺部疾病建模、组织工程和转化研究哈佛医学院和哈佛大学。研究：特发性肺纤维化（IPF）是一种进行性疤痕性肺部疾病，常导致呼吸衰竭。对有效疗法的需求仍有大量未得到满足。特发性肺纤维化被认为是由对重复性组织损伤的功能失调的伤口愈合反应引起的。血管通透性增加是主要的伤口愈合反应，这在肺部允许血浆蛋白从肺血管系统泄漏到空气空间中。增加已在 IPF 患者的肺部显示出渗透性，并可预测死亡率。我们建议通过抑制内皮细胞来恢复肺损伤后的内皮屏障功能 ROCK 激活或增强内皮细胞 S1P1 激活，可以提供一种新颖且减轻肺纤维化发展的具体治疗策略。