Epilysin in Lung Immunity

这项建议概述了一项为期5年的培训计划，以培养一名在以下领域的医生-科学家 肺内科。拟议培训计划的目标是提供必要的技能以使用 现代生物学工具，以解决与肺部疾病和炎症有关的基本问题。这 课程包括正式的教学，参加期刊俱乐部，在地方和全国会议上发表演讲 以及手稿的准备和出版。首席调查员将由威廉博士指导 帕克斯不仅拥有指导成功资助的独立调查人员的丰富经验，而且 也是他在基质金属蛋白酶(MMP)生物学、组织损伤和修复领域的领先者。 科学计划的重点将是确定一种新发现的基质金属蛋白酶的作用和底物， 在肺损伤和炎症方面。对Eepysin缺失小鼠的初步研究表明，早期 巨噬细胞在感染期间重新聚集到肺中，并表明外切蛋白是一种负调控因子 用于巨噬细胞的流入。这项建议的第一个目标是表征炎性表型。 Eepysin缺失的小鼠。我们将通过以下方式验证我们的假设，即外切蛋白是巨噬细胞内流的关键效应因子 评估几种肺和腹膜损伤/炎症模型。我们的第二个目标将决定 巨噬细胞凝集素调节巨噬细胞重新聚集到肺内的粘附素的细胞来源。通过生成嵌合体 通过小鼠骨髓移植，我们将检验我们的假设，即巨噬细胞衍生的外切蛋白控制 巨噬细胞涌入。我们的第三个目标将确定外切蛋白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外切酶的底物(S)，我们 假设是巨噬细胞表面蛋白，如趋化因子受体或黏附蛋白。 这些研究将促进我们对巨噬细胞内流是如何调节和抑制的理解， 从而确定了限制过度旺盛炎症的内在机制。所获得的知识 本研究对认识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来 为调查员提供必要的工具，使其成为实地成功的独立调查员 肺医学部。

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.