Mechanisms and Antigen Identification in a Novel Model of Autoimmune Lung Disease

自身免疫性肺病新模型的机制和抗原鉴定

基本信息

批准号：
8504518
负责人：
Anthony Shum
金额：
$ 12.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504518
关键词：
Accounting Address Adoptive Transfer Alleles Animal Model Animals Antibodies Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Biological Assay Biological Markers Blood Tests Bronchiolitis Bronchiolitis Obliterans Organizing Pneumonia California Cell Cycle Kinetics Cells Clinical Complication Critical Care Data Defect Development Development Plans Diagnosis Disease Dose Environment Experimental Models Failure Fibrosis Foundations Future Genes Goals Grant Homologous Gene Human Human Cloning Immune Immune Tolerance Immune response Immunoblotting Immunohistochemistry Immunology Immunosuppression Injury Interstitial Lung Diseases Interstitial Pneumonia Knockout Mice Laboratories Lead Learning Life Lung Lung Transplantation Lung diseases Lymphoid interstitial pneumonia Mediating Mentors Modeling Mouse Protein Mus Mutation Organ Pathogenesis Patients Pattern Peptide/MHC Complex Phenotype Physicians Population Principal Investigator Proteins Pulmonary Fibrosis Radioimmunoassay Regulator Genes Research Research Personnel Rheumatoid Arthritis Risk Role San Francisco Scientist Scleroderma Serum Severities Structure of parenchyma of lung Syndrome T-Lymphocyte Testing Therapeutic Thymus Gland Training Training Programs Transgenic Organisms Translating Translational Research Universities Variant Vascular Diseases Work aged authority autoreactive T cell base career career development cell type cohort cytokine design disease mechanisms study effective therapy experience fundamental research gene cloning immunopathology immunoreactivity injured interstitial lung development lung injury mouse model novel outcome forecast professor research study response skills systemic autoimmune disease therapy design thymocyte tool

项目摘要

Pulmonary disease is a frequent complication of systemic autoimmune diseases, often requiring aggressive treatment with high dose immunosuppression or lung transplantation. Despite the significant clinical impact, little is understood about the pathogenesis of lung disease in autoimmune conditions. As a pulmonary and critical care physician at the University of California, San Francisco, Dr. Anthony Shum is establishing himself as an investigator in the mechanisms of autoimmune-mediated lung disease. With the highly regarded Immunology Training Program and an internationally recognized mentoring team, UCSF provides the ideal environment for the critical studies and intensive training necessary for Dr. Shum's development towards his long-term goal of a career as a physician-scientist. The primary mentor, Dr. Mark Anderson, is a leading expert in central immune tolerance, and co-mentor, Dr. Harold Chapman, Professor and Chief of the Pulmonary Division, is a renowned authority on lung injury and tissue remodeling. A major barrier to research on lung autoimmunity has been the lack of animal models in which to study disease pathogenesis. Using the Aire (Autoimmune Regulator) deficient mouse, Dr. Shum's research presents the unique opportunity to define basic mechanisms of autoimmune lung disease in a novel model of a known human autoimmune syndrome. Autoimmune Polyglandular Syndrome 1 (APS1) arises from mutations in the AIRE gene and like their human counterparts, Aire deficient mice develop autoimmunity to multiple organs, including the lung, due to a critical breakdown in central immune tolerance. Importantly, Aire deficient mice develop interstitial lung disease spontaneously in a pattern strikingly similar to APS1 patients. Furthermore, Dr. Shum has identified a novel lung autoantigen in the Aire deficient mouse that may be the key to initiating disease. Thus, we hypothesize that pulmonary disease in Aire KO mice is due to a failure to tolerize thymocytes to a critical lung antigen, resulting in the escape of autoreactive T cells that target and injure the lung. To address this hypothesis, the proposed specific aims are to: (1) determine the cell populations that mediate lung disease in Aire KO mice; (2) establish the role of our lung antigen in the pathogenesis of pulmonary disease in the mouse model; and (3) establish the role of the human homolog of RELEVANCE (Seeinstructions). In this project we will learn how lung damage occurs in systemic autoimmune diseases like rheumatoid arthritis or scleroderma. We will identify the cells that are attacking the lung, which lung proteins they are targeting, and how they cause injury. In doing so, we will be able to develop blood tests to help physicians diagnose patients with autoimmune lung disease and determine their prognosis. We also seek to design therapies made specifically for the lung to effectively treat patients with these disorders.

肺部疾病是全身性自身免疫性疾病的常见并发症，通常需要采用大剂量免疫抑制剂或肺移植进行积极治疗。尽管意义重大临床影响，人们对自身免疫性疾病中肺部疾病的发病机制知之甚少。作为一个加州大学旧金山分校的肺科和重症监护医师 Anthony Shum 博士是使自己成为自身免疫介导的肺部疾病机制的研究者。随着备受推崇的免疫学培训计划和国际认可的指导团队，UCSF 为沉博士的批判性研究和强化培训提供了理想的环境朝着成为一名医师科学家的长期职业目标发展。主要导师Mark博士安德森（Anderson）是中枢免疫耐受领域的领先专家，共同导师哈罗德·查普曼（Harold Chapman）教授肺科主任，是肺损伤和组织重塑方面的著名权威。肺自身免疫研究的一个主要障碍是缺乏可供研究的动物模型疾病发病机制。 Shum 博士使用 Aire（自身免疫调节器）缺陷小鼠进行的研究提供了在新模型中定义自身免疫性肺病基本机制的独特机会一种已知的人类自身免疫综合症。自身免疫性多腺体综合征 1 (APS1) 源自 AIRE 基因突变，与人类同类一样，Aire 缺陷小鼠会产生自身免疫由于中枢免疫耐受的严重崩溃，包括肺在内的多个器官。重要的是， Aire 缺陷小鼠自发发生间质性肺疾病，其模式与 APS1 惊人相似患者。此外，Shum 博士在 Aire 缺陷小鼠中发现了一种新的肺自身抗原，该抗原可能成为引发疾病的关键。因此，我们假设 Aire KO 小鼠的肺部疾病是由于胸腺细胞无法耐受关键的肺抗原，导致自身反应性 T 细胞逃逸，瞄准并损伤肺部。为了解决这一假设，提出的具体目标是：（1）确定介导 Aire KO 小鼠肺部疾病的细胞群； (2) 确定我们的肺抗原在小鼠模型中肺部疾病的发病机制； (3) 确定人类同源物的作用相关性（参见说明）。在这个项目中，我们将了解系统性自身免疫性疾病中肺损伤是如何发生的类风湿性关节炎或硬皮病等疾病。我们将识别攻击肺部的细胞，它们针对的肺部蛋白质以及它们如何造成损伤。这样做，我们就能开发血液帮助医生诊断患有自身免疫性肺病的患者并确定其预后的测试。我们还寻求设计专门针对肺部的疗法，以有效治疗患有这些疾病的患者。