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）： 该提案概述了一项为期5年的培训计划，以开发肺医学领域的医师科学家。拟议的培训计划的目的是提供使用现代生物学工具来解决基本问题相关的肺部疾病和炎症所需的技能。该计划包括正式的教学，参与期刊俱乐部，在本地和国家会议上的演讲以及手稿准备和出版。首席研究人员将由威廉·帕克斯（William Parks）博士进行指导，威廉·帕克斯（William Parks）不仅拥有丰富的经验，这些经验是成功资助的独立研究人员，而且还是他的基质金属蛋白酶（MMP）生物学，组织损伤和维修领域的领导者。该科学计划将着重于确定新鉴定的MMP epilysin在肺损伤和炎症中的作用和底物。在撒丽氏无效小鼠中的初步研究表明，感染期间巨噬细胞募集到肺的早期募集增加，并表明epilysin是巨噬细胞涌入的负调节剂。该提案的第一个目的是表征亚志氏菌无小鼠中的炎症表型。我们将通过评估肺部和腹膜中的几种损伤/炎症模型来检验假设，即epilysin是巨噬细胞流入的关键效应因子。我们的第二个目标将确定子叶叶蛋白的细胞来源，该细胞来调节巨噬细胞募集到肺部。通过通过骨髓移植产生嵌合小鼠，我们将测试巨噬细胞衍生的撒乳蛋白控制巨噬细胞涌入的假设。我们的第三个目标将确定子叶蛋白酶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子叶蛋白酶的底物，我们认为这是巨噬细胞表面蛋白，例如趋化因子受体或粘合蛋白。这些研究将通过识别限制过度发炎的内在机制来提高我们对巨噬细胞涌入如何受到调节和约束的理解。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。该应用程序利用了华盛顿大学提供的资源和指导，为研究人员提供了成为肺医学领域成功的独立研究者所需的工具。 （抽象的结尾）