Epilysin in Lung Immunity

Epilysin 在肺部免疫中的作用

基本信息

批准号：
7787069
负责人：
Anne M. Manicone
金额：
$ 12.68万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7787069
关键词：
Acute Address Adhesives Affect Alveolar Animals Biological Biology Bone Marrow Bone Marrow Transplantation CXC Chemokines Cell Surface Proteins Cell model Cells Chemotactic Factors Complex Disease Epithelial Epithelial Cells Family Funding Health Homeostasis Immune system Immunity Infection Inflammation Inflammatory Inflammatory Response Injury Journals Knock-out Knockout Mice Knowledge Laboratories Leukocyte Trafficking Leukocytes Lung Lung diseases MMP-28 Manuscripts Matrilysin Matrix Metalloproteinases Mediating Mentors Modeling Mus Natural Immunity Neutrophilia Peptide Hydrolases Peritoneum Peritonitis Phase Phenotype Physicians Pneumonia Preparation Principal Investigator Process Program Development Proteins Proteoglycan Proteolytic Processing Pseudomonas aeruginosa Publications Pulmonology Regulation Research Research Personnel Resources Role Scientist Source Testing Tissues Training Training Programs Universities Washington aerosolized chemokine chemokine receptor design experience improved injury and repair interstitial lung injury macrophage meetings member migration neutrophil programs reconstitution skills syndecan tool

项目摘要

This proposal outlines a 5-year training program for the development of a physician-scientist in the field of Pulmonary Medicine. The objective of the proposed training plan is to provide the skills necessary to use modern biological tools to address basic questions related pulmonary disease and inflammation. This program includes formal didactics, participation in journal clubs, presentation at local and national meetings and manuscript preparation and publication. The principal investigator will be mentored by Dr. William Parks, who not only has extensive experience mentoring successfully-funded independent investigators, but also is a leader in his field of matrix metalloproteinase (MMP) biology, tissue injury and repair. The scientific program will focus on identifying the role and substrate of a newly identified MMP, epilysin, in lung injury and inflammation. Preliminary studies in epilysin-null mice reveal an increase in early macrophage recruitment to the lung during infection and indicate that epilysin serves as a negative regulator for macrophage influx. The first aim of this proposal is to characterize the inflammatory phenotype in epilysin-null mice. We will test our hypothesis that epilysin is a key effector of macrophage influx, by assessing several models of injury/inflammation in the lung and peritoneum. Our second aim will determine the cellular source of epilysin that regulates macrophage recruitment into the lungs. By generating chimeric mice via bone marrow transplantation, we will test our hypothesis that macrophage-derived epilysin controls macrophage influx. Our third aim will determine the mechanism by which epilysin mediates macrophage recruitment. We plan to use animal and cell models to determine epilysin's substrate(s), which we hypothesize is a macrophage cell surface protein, such as a chemokine receptor or adhesive protein. These studies will advance our understanding of how macrophage influx is regulated and restrained, thereby identifying an intrinsic mechanism that limits over-exuberant inflammation. The knowledge gained from this research will have important implications in understanding and treating inflammatory diseases. This application takes advantage of the resources and mentoring available at the University of Washington to provide the investigator with the tools necessary to become a successful independent investigator in the field of Pulmonary Medicine.

该提案概述了一项为期5年的培训计划，用于开发该领域的医师科学家肺医学。拟议的培训计划的目的是提供使用必要的技能现代生物学工具，以解决有关肺部疾病和炎症的基本问题。这计划包括正式的教学，参加期刊俱乐部，在本地和国家会议上的演讲以及手稿的准备和出版物。首席调查员将由威廉博士指导公园不仅有丰富的经验，在成功资助的独立调查员中，而且也是他的基质金属蛋白酶（MMP）生物学，组织损伤和修复领域的领导者。科学计划将着重于确定新确定的MMP Epilysin的角色和底物，在肺损伤和炎症中。 epilysin-null小鼠的初步研究表明早期有所增加巨噬细胞在感染期间募集到肺部，并表明epilysin是负调节剂用于巨噬细胞涌入。该提议的第一个目的是表征 epilysin-null小鼠。通过评估肺和腹膜中的几种损伤/炎症模型。我们的第二个目标将决定子叶叶蛋白的细胞来源调节巨噬细胞募集到肺部。通过产生嵌合小鼠通过骨髓移植，我们将测试巨噬细胞衍生的子叶苷对照的假设巨噬细胞涌入。我们的第三个目标将确定epilysin介导巨噬细胞的机制招聘。我们计划使用动物和细胞模型来确定epilysin的底物，我们假设是巨噬细胞表面蛋白，例如趋化因子受体或粘合剂蛋白。这些研究将促进我们对如何调节和约束巨噬细胞涌入的理解，从而确定一种内在机制，该机制限制了过度炎症的炎症。知识获得了从这项研究中，将对理解和治疗炎症性疾病具有重要意义。该应用程序利用华盛顿大学提供的资源和指导为研究人员提供成为成功的独立研究者所需的工具肺部医学。