Immune Activation of Fibroblasts

成纤维细胞的免疫激活

基本信息

批准号：
7490434
负责人：
RAYMOND S DOUGLAS
金额：
$ 17.93万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-27 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7490434
关键词：
Address Anatomy Antibody Activation Autoantigens Autoimmune Diseases Autoimmune Process Binding Biological Biological Assay Biological Models Cells Characteristics Chemotactic Factors Clinical Clinical Research Condition Connective Tissue Disease Event Fibroblasts Genes Graves&apos Disease Growth Factor IgG Receptors Immune Immunoglobulin G In Vitro Infiltration Inflammatory Response Insulin Insulin-Like-Growth Factor I Receptor Interleukin-16 K-Series Research Career Programs Laboratories Ligands Link Mediating Mediator of activation protein Mentors Mus Nuclear Ocular orbit Pathogenesis Patients Pattern Play Problem Solving Production RANTES Recruitment Activity Relative (related person)Research Research Personnel Role Running SCID Mice Serum Severities Signal Transduction Source T-Lymphocyte Testing Thinking Thyroid Gland Tissues Up-Regulation Work beta-Chemokines cell motility clinically relevant in vivo knowledge base mRNA Stability mouse model promoter receptor skills

项目摘要

DESCRIPTION (provided by applicant): Fibroblast activation plays an important role in initiating the inflammatory response. Phenotypic attributes of fibroblasts from specific anatomic regions are thought to underlie the peculiar pattern of manifestations associated with certain disease. Other fibroblast characteristics appear global, such as the expression of chemoattractants including IL-16, a CD4-specific ligand and RANTES, a C-C chemokine. We have found that fibroblasts from patients with Graves' disease (GD), when treated with their IgGs (GD-IgG), become activated and express high levels of IL-16 and RANTES. Control fibroblasts from donors without autoimmune disease fail to respond to these IgGs. GD-IgG which are disease specific, appear to be binding to the insulin-like growth factor 1 receptor (IGF-1R) displayed on fibroblasts. We hypothesize that IGF-1R represents an important activational self-antigen. We now propose the following studies to test our central hypothesis. 1) To define the mechanism(s) involved in the GD-specific anti IGF-1R IgG upregulation of IL-16 and RANTES expression by fibroblasts; 2) To determine the serum levels of GD-IgG, IL-16 and RANTES in autoimmune graves disease patients and normal controls and determine the clinical utility of these parameters; 3) To test in vivo the hypothesis that IGF-1R is a critical self-antigen in GD that when ligated with GD-IgG, activates IL-16 and RANTES expression and T cell infiltration. The candidate and mentor have worked closely together for the last year in a productive relationship. The research career development award, continued mentoring and the availability of the General Clinical Research Center, will allow the candidate to further investigate and answer these clinically relevant questions. The candidate will develop the scientific knowledge base, problem solving abilities and technical skills to develop into an independent researcher.

描述（由申请人提供）：成纤维细胞活化在引发炎症反应中起着重要作用。来自特定解剖区域的成纤维细胞的表型属性被认为是与某些疾病相关的特殊表现模式的基础。其他成纤维细胞特征似乎是全局性的，例如趋化剂的表达，包括 IL-16（一种 CD4 特异性配体）和 RANTES（一种 C-C 趋化因子）。我们发现，格雷夫斯病 (GD) 患者的成纤维细胞在接受 IgG (GD-IgG) 治疗后会被激活并表达高水平的 IL-16 和 RANTES。来自没有自身免疫性疾病的供体的对照成纤维细胞无法对这些 IgG 产生反应。 GD-IgG 是疾病特异性的，似乎与成纤维细胞上展示的胰岛素样生长因子 1 受体 (IGF-1R) 结合。我们假设 IGF-1R 代表一种重要的激活性自身抗原。我们现在提出以下研究来检验我们的中心假设。 1) 明确 GD 特异性抗 IGF-1R IgG 上调成纤维细胞 IL-16 和 RANTES 表达的机制； 2) 测定自身免疫性格雷夫斯病患者和正常对照者的血清GD-IgG、IL-16和RANTES水平，并确定这些参数的临床实用性； 3) 体内测试IGF-1R是GD中关键的自身抗原的假设，当与GD-IgG连接时，激活IL-16和RANTES表达以及T细胞浸润。去年，候选人和导师密切合作，建立了富有成效的关系。研究职业发展奖、持续指导和普通临床研究中心的可用性将使候选人能够进一步调查和回答这些临床相关问题。候选人将发展科学知识基础、解决问题的能力和技术技能，以发展成为一名独立的研究员。