Epilysin in Lung Immunity

该提案概述了一项为期5年的培训计划，旨在培养医学科学家， 肺内科拟议培训计划的目标是提供必要的技能， 现代生物学工具来解决与肺部疾病和炎症相关的基本问题。这 课程包括正式的教学法，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博士指导 帕克斯不仅拥有指导成功资助独立调查人员的丰富经验， 也是基质金属蛋白酶（MMP）生物学、组织损伤和修复领域的领导者。 科学计划将集中在确定一个新发现的MMP，epilysin的作用和底物， 肺损伤和炎症。对癫痫素缺失小鼠的初步研究显示， 巨噬细胞募集到肺部感染，并表明，癫痫溶解素作为一个负调节 巨噬细胞流入。该建议的第一个目的是表征在人乳腺癌中的炎性表型。 epilysin无效小鼠。我们将检验我们的假设，即epilysin是巨噬细胞流入的关键效应子， 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 调节巨噬细胞向肺中募集的癫痫溶解素的细胞来源。通过产生嵌合的 小鼠骨髓移植，我们将测试我们的假设，巨噬细胞源性癫痫溶解素控制 巨噬细胞内流我们的第三个目标是确定癫痫溶解素介导巨噬细胞 招聘我们计划使用动物和细胞模型来确定epilysin的底物， 假设是巨噬细胞表面蛋白，如趋化因子受体或粘附蛋白。 这些研究将促进我们对巨噬细胞内流是如何被调节和抑制的理解， 从而确定限制过度增生炎症的内在机制。获得的知识 这项研究将对理解和治疗炎症性疾病有重要意义。 此应用程序利用华盛顿大学提供的资源和指导， 为调查员提供必要的工具，使其成为该领域成功的独立调查员 肺内科

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.