Epilysin in Lung Immunity

描述(由申请人提供)： 这项建议概述了一项为期5年的培训计划，以培养一名肺部医学领域的内科科学家。拟议培训计划的目标是提供必要的技能，利用现代生物工具解决与肺部疾病和炎症有关的基本问题。该计划包括正式的教学，参加期刊俱乐部，在地方和国家会议上发表演讲，以及手稿的准备和出版。首席研究员将由威廉·帕克斯博士指导，他不仅拥有指导成功资助的独立调查人员的丰富经验，而且是其所在领域的基质金属蛋白酶(MMP)生物学、组织损伤和修复领域的领导者。这项科学计划将侧重于确定一种新发现的基质金属蛋白酶--外切素在肺损伤和炎症中的作用和底物。对Epeysin缺失小鼠的初步研究显示，感染期间早期巨噬细胞向肺内募集的增加，并表明Epeysin对巨噬细胞内流起到负调节作用。这项建议的第一个目的是表征Eepysin缺失小鼠的炎症表型。我们将通过评估肺和腹膜的几种损伤/炎症模型来验证我们的假设，即外切蛋白是巨噬细胞内流的关键效应因子。我们的第二个目标将确定调节巨噬细胞重新聚集到肺中的外切蛋白的细胞来源。通过骨髓移植产生嵌合小鼠，我们将检验我们的假设，即巨噬细胞来源的Eepysin控制巨噬细胞的内流。我们的第三个目标将确定外切蛋白介导巨噬细胞募集的机制。我们计划使用动物和细胞模型来确定外切蛋白的底物(S)，我们假设它是一种巨噬细胞表面蛋白，如趋化因子受体或黏附蛋白。这些研究将通过识别限制过度活跃的炎症的内在机制，促进我们对巨噬细胞内流是如何被调节和抑制的理解。这项研究获得的知识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可用的资源和指导，为研究人员提供必要的工具，使其成为肺部医学领域的一名成功的独立研究人员。(摘要结束)

DESCRIPTION (provided by applicant): 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, there by 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. (End of Abstract)