权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanism(s) of TCE-Mediated Autoimmunity

TCE 介导的自身免疫机制

基本信息

批准号：
7929076
负责人：
GHULAM A.S. ANSARI
金额：
$ 3.66万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-20 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929076
关键词：
Address Affinity Amino Acid Sequence Antibodies Antigen-Antibody Complex Antigens Antinuclear Antibodies Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Cell Activation B-Lymphocytes Binding Binding Proteins Cardiolipins Cell Proliferation Cell physiology Cells Chemical Exposure Chemicals Chloride Ion Chlorides Classification Data Databases Dependence Dichloroacetic Acid Disease Dose Early Diagnosis Electrospray Ionization Environmental Pollution Exposure to Female Flow Cytometry Future Genetic Predisposition to Disease Goals Histones IgG1 IgG3 Immunoglobulin G Intervention Literature Lymphocyte Measures Mediating Medical Memory Metabolism Modeling Mole the mammal Mus N-terminal Nuclear Oxides Peptide Fragments Preventive Production Proteins Reaction Time Role Scleroderma Serum Severities Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Systemic Lupus Erythematosus T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Time Tissues Trichloroacetic Acid Trichloroethylene Western Blotting adduct anti-IgG autoreactive T cell base cytokine design drinking water environmental chemical insight killings prevent response tandem mass spectrometry trichloroacetaldehyde

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to elucidate the mechanism(s) by which environmental chemicals induce diseases so that preventive therapies and/or interventions can be devised. Trichloroethene (trichloroethylene, TCE), an environmental contaminant, is implicated in causing autoimmune-like diseases. However, no systematic studies have yet established its potential in inducing/exacerbating such diseases, or elucidated the mechanism(s) to TCE-induced autoimmunity, which is the focus of this application. Based upon the literature and our preliminary studies, we hypothesize that TCE and/or its metabolites bind to endogenous protein(s). These protein adducts elicit T and B cell responses that escape the normal tolerance to self-protein(s), leading to autoimmune-like diseases. This hypothesis will be tested by pursuing four Specific Aims: 1) To determine the autoimmune potential of TCE by conducting dose-and time-dependent studies in female MRL+/+ mice; autoimmune responses will be assessed by measuring autoantibodies and TCE-specific antibodies, circulating immune complexes, alterations in T cell functions, and by examining morphological changes. 2) To address the contribution of TCE metabolites to the induced autoimmunity, autoimmune responses to TCE-metabolites will be examined. 3) To identify the protein adduct(s) [antigen(s)] of TCE responsible for autoimmune responses. Protein adduct(s) will be purified from major tissues and characterized, and their autoimmune potential will be tested in mice. 4) To examine the role of T cells in TCE-induced autoimmune response. T cell responses (e.g., cell proliferation and the production of cytokines) to TCE and its protein-adducts(s) will be assessed. These studies should establish that TCE induces autoimmunity and provide insights into the mechanism(s) responsible for these responses. Our results will be important in designing strategies to prevent or reduce autoimmune responses to TCE and other related industrial chemicals. Furthermore, elucidating the mechanism(s) of TCE-induced autoimmunity will open avenues for early detection, medical interventions or therapies to prevent or manage various chemical-induced autoimmune diseases.

描述（由申请人提供）：我们的长期目标是阐明环境化学物质诱发疾病的机制，以便设计预防性治疗和/或干预措施。三氯乙烯（三氯乙烯，TCE）是一种环境污染物，与引起自身免疫性疾病有关。然而，尚未有系统研究证实其诱发/加剧此类疾病的潜力，或阐明 TCE 诱发自身免疫的机制，而这正是本申请的重点。根据文献和我们的初步研究，我们假设 TCE 和/或其代谢物与内源蛋白结合。这些蛋白质加合物引发 T 和 B 细胞反应，逃避对自身蛋白质的正常耐受性，从而导致自身免疫性疾病。这一假设将通过四个具体目标进行检验：1) 通过在雌性 MRL+/+ 小鼠中进行剂量和时间依赖性研究来确定 TCE 的自身免疫潜力；将通过测量自身抗体和 TCE 特异性抗体、循环免疫复合物、T 细胞功能的改变以及检查形态变化来评估自身免疫反应。 2) 为了解决 TCE 代谢物对诱导自身免疫的贡献，将检查对 TCE 代谢物的自身免疫反应。 3) 鉴定负责自身免疫反应的TCE蛋白加合物[抗原]。蛋白质加合物将从主要组织中纯化并表征，并将在小鼠中测试其自身免疫潜力。 4) 检查T细胞在TCE诱导的自身免疫反应中的作用。将评估 T 细胞对 TCE 及其蛋白质加合物的反应（例如细胞增殖和细胞因子的产生）。这些研究应该证实 TCE 会诱导自身免疫，并提供对导致这些反应的机制的见解。我们的结果对于设计预防或减少对 TCE 和其他相关工业化学品的自身免疫反应的策略非常重要。此外，阐明三氯乙烯引起的自身免疫性疾病的机制将为早期检测、医疗干预或治疗开辟途径，以预防或控制各种化学物质引起的自身免疫性疾病。