权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10223415
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/10223415
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 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 Universities Vascular Permeabilities Work career cell injury design drug development edg-1 Protein effective therapy epithelial injury 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 therapeutically effective three dimensional cell culture tissue injury translational research program wound healing

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.

项目摘要候选人：Rachel Wampe，医学博士，是一名内科医生，在肺和重症监护科，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经验肺纤维化，重点是ROCK，S1P1和肌动蛋白细胞骨架的作用，纤维化该K08应用旨在了解血管通透性在血管通透性中的作用。肺纤维化的发展，研究两种相反的渗透性调节因子，ROCK S1P1。她的短期目标是获得内皮生物学，动物模型，人类肺病、微工程培养系统和转化研究。她长长长期目标是领导一个关于血管渗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位置Dr.Dallpe为她的第一个R01和一个独立的职业生涯作为一个物理学家，科学家。导师制、培训活动和环境：Dr. Alfrepe将执行在肺和重症监护医学部的指导下， Drs.本杰明·梅塞尔和安德鲁·卢斯特梅瑟和卢斯特博士都有在肺部疾病小鼠模型和转化研究方面的经验和优秀记录的指导。廖建邦博士、何立峰博士、陈晓波博士及巴里谢伊博士将担任本中心的顾问。提供ROCK和S1P1信号、鼠标、肺部疾病的建模，利用先进的微工程培养系统的细胞生物学和翻译研究。Dr. Alberpe将完成内皮生物学、小鼠人类肺部疾病的建模，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）是一种进行性瘢痕性肺病，经常导致呼吸衰竭。仍然存在对有效疗法的大量未满足的需求。IPF 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驱动的。血管通透性增加是一种主要的伤口愈合反应，在肺中，血浆蛋白从肺血管渗漏到空气中。增加在IPF患者的肺中已经显示出渗透性，并且预测死亡率。我们提出肺损伤后恢复内皮屏障功能， ROCK激活或增强内皮细胞S1P1激活，可以提供一种新的，特异性治疗策略以减轻肺纤维化的发展。