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：
7883278
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7883278
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 Bronchiolitis Bronchiolitis Obliterans Organizing Pneumonia California Cell Cycle Kinetics Cells Clinical Complication Critical Care Data Defect Development Development Plans 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 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 Syndrome T-Lymphocyte Testing Therapeutic Thymus Gland Tissues 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 professor research study response skills systemic autoimmune disease thymocyte tool

项目摘要

DESCRIPTION (provided by applicant): 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 our antigen and demonstrate APS1 and ILD patient immunoreactivity.

描述（由申请人提供）：肺部疾病是全身性自身免疫性疾病的常见并发症，通常需要大剂量免疫抑制或肺移植的积极治疗。尽管具有重大的临床影响，但人们对自身免疫性疾病中肺部疾病的发病机制知之甚少。作为加州大学旧金山分校的肺部和重症监护医师，Anthony Shum 博士正在将自己定位为自身免疫介导的肺部疾病机制的研究者。凭借备受推崇的免疫学培训计划和国际认可的指导团队，加州大学旧金山分校为岑博士实现其作为医师科学家职业生涯的长期目标所必需的批判性研究和强化培训提供了理想的环境。主要导师马克·安德森博士是中枢免疫耐受方面的顶尖专家，副导师哈罗德·查普曼博士是肺科教授兼主任，是肺损伤和组织重塑领域的著名权威。肺部自身免疫研究的一个主要障碍是缺乏研究疾病发病机制的动物模型。 Shum 博士的研究利用 Aire（自身免疫调节器）缺陷小鼠进行研究，为在已知人类自身免疫综合征的新模型中定义自身免疫性肺病的基本机制提供了独特的机会。自身免疫性多腺综合症 1 (APS1) 是由 AIRE 基因突变引起的，与人类同类一样，由于中枢免疫耐受严重崩溃，Aire 缺陷小鼠会对包括肺在内的多个器官产生自身免疫。重要的是，Aire 缺陷小鼠会自发发生间质性肺疾病，其模式与 APS1 患者惊人相似。此外，Shum 博士在 Aire 缺陷小鼠中发现了一种新型肺自身抗原，它可能是引发疾病的关键。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部抗原，导致靶向并损伤肺部的自身反应性 T 细胞逃逸。为了解决这一假设，提出的具体目标是：（1）确定在 Aire KO 小鼠中介导肺部疾病的细胞群； (2)在小鼠模型中建立我们的肺抗原在肺部疾病发病机制中的作用； (3) 确定我们抗原的人类同源物的作用并证明 APS1 和 ILD 患者的免疫反应性。