Epilysin in Lung Immunity

Epilysin 在肺部免疫中的作用

• 批准号: 7211459
• 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
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211459
• 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; Endopeptidases; 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; abstracting; aerosolized; chemokine; chemokine receptor; design; experience; improved; injury and repair; interstitial; lung injury; macrophage; member; migration; neutrophil; programs; reconstitution; skills; syndecan; tool

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)

描述（由申请人提供）： 该提案概述了一个为期5年的培训计划，用于培养肺医学领域的医生-科学家。拟议培训计划的目标是提供使用现代生物工具解决与肺部疾病和炎症有关的基本问题所需的技能。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的演讲以及手稿的准备和出版。主要研究者将由William Parks博士指导，他不仅拥有指导成功资助的独立研究者的丰富经验，而且是基质金属蛋白酶（MMP）生物学，组织损伤和修复领域的领导者。该科学计划将集中于确定一种新发现的MMP，epilysin在肺损伤和炎症中的作用和底物。在epilysin-null小鼠中的初步研究揭示了在感染期间早期巨噬细胞向肺的募集增加，并且表明epilysin充当巨噬细胞流入的负调节剂。该建议的第一个目的是表征癫痫溶解素缺失小鼠的炎症表型。我们将通过评估肺和腹膜中的几种损伤/炎症模型来检验我们的假设，即癫痫溶解素是巨噬细胞流入的关键效应子。我们的第二个目标是确定调节巨噬细胞募集到肺部的epilysin的细胞来源。通过骨髓移植产生嵌合体小鼠，我们将测试我们的假设，巨噬细胞源性的epilysin控制巨噬细胞流入。我们的第三个目标是确定癫痫溶解素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epilysin的底物，我们假设它是巨噬细胞表面蛋白，如趋化因子受体或粘附蛋白。这些研究将通过确定限制过度旺盛炎症的内在机制，促进我们对巨噬细胞流入如何被调节和抑制的理解。从这项研究中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的资源和指导，为研究者提供必要的工具，使其成为肺医学领域成功的独立研究者。(End摘要）