Oxidative Stress and Autoimmunity

氧化应激和自身免疫

基本信息

批准号：
8197373
负责人：
M. FIROZE KHAN
金额：
$ 31.45万
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：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197373
关键词：
3-nitrotyrosine 4 hydroxynonenal Acetylcysteine Aldehydes Antibodies Antigen-Antibody Complex Antinuclear Antibodies Antioxidants Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Binding Cardiolipins Cell Respiration Chemical Exposure Chemicals Clinical Cytochrome P-450 CYP2E1 Dependence Deposition Development Diet Disease Disease Marker Disease Progression Dose Enzyme-Linked Immunosorbent Assay Enzymes Exposure to Genetic Glomerulonephritis Goals Human Immune response Immunohistochemistry Intervention Iron Overload Kidney Kinetics Knock-out Life Link Lipid Peroxidation Liver Malondialdehyde Mediating Medical Surveillance Messenger RNA Modification Mus Names Nitrates Nitrogen Nuclear Oxidative Stress Oxygen Pathogenesis Patients Prevention Preventive Principal Investigator Production Proteins Proteomics Public Health Reactive Nitrogen Species Reporting Research Resistance Risk Assessment Role Scleroderma Serum Spleen Superoxide Dismutase Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Time Tissues Trichloroethylene Vasculitis adduct antigen processing base catalase design environmental chemical glutathione peroxidase human NOS2A protein indexing inhibitor/antagonist insight iron supplement macromolecule mouse model nitration nitrosative stress oxidation programs response systemic autoimmune disease translational approach

项目摘要

DESCRIPTION (provided by applicant): Environmental chemicals are implicated as causative agents of autoimmune diseases (ADs). Our long-term goal is to elucidate the role of lipid peroxidation-derived aldehydes (LPDAs) and reactive nitrogen species (RNS) in the development of ADs induced and/or exacerbated by chemical exposure. Increased production of reactive oxygen and nitrogen species (RONS) has been implicated in the pathogenesis of ADs, and a large number of chemicals are known to produce RONS. Correspondingly, increased lipid peroxidation and protein nitration are also reported in systemic ADs. We hypothesize that increased production of LPDAs and RNS causes structural alterations to endogenous macromolecules, including proteins, through covalent binding and/or oxidation, resulting in the formation of neoantigens. Following antigen processing, these neoantigens can elicit autoimmune responses by stimulating T and B lymphocytes, eventually leading to ADs such as systemic lupus erythematosus (SLE). This hypothesis will be tested through four specific aims to: 1) Delineate the link between oxidative stress and autoimmunity. This will be achieved by exposing autoimmune-prone (MRL+/+) and -resistant (B6C3F1) mice to trichloroethene (TCE, an environmental chemical known to cause lipid peroxidation/RNS). Formation of LPDA-protein adducts (in liver, kidney and spleen) and their corresponding antibodies will be correlated with autoimmune response. The role of oxidative stress in autoimmunity will be further established through iron overload, N-acetylcysteine administration and use of CYP2E1 knockout MRL +/+ mice; 2) Establish the role of RNS induced by TCE in autoimmunity. Using iNOS inhibitors and iNOS knockout MRL +/+ mice, we will evaluate the potential of RNS in leading to autoimmunity; 3) Elucidate the mechanism(s) of autoimmunity resulting from lipid peroxidation. Utilizing LPDA-protein adducts, the role of T cells in autoimmunity will be elucidated; 4) Define oxidative/nitrosative stress signature in the sera of SLE patients. Using sera from SLE patients, a link between oxidative stress markers and disease progression will be established. Our studies should establish oxidative stress as a pathogenic mechanism of ADs, and open important avenues for clinical intervention and medical surveillance through the development of disease markers, and will provide an avenue for mechanism-based risk assessment. Relevance to Public Health: Autoimmune diseases are serious pathological conditions with unknown cause. Our goal is to elucidate the role of oxidative and nitrosative stress in the development of such diseases. The results of this study will provide important insight into the prevention and management of such diseases.

描述（由申请人提供）：环境化学物质被认为是自身免疫性疾病（AD）的病原体。我们的长期目标是阐明脂质过氧化衍生醛 (LPDA) 和活性氮 (RNS) 在化学暴露诱导和/或加剧的 AD 发展中的作用。活性氧和活性氮 (RONS) 产生的增加与 AD 的发病机制有关，并且已知大量化学物质会产生 RONS。相应地，在全身性 AD 中也报道了脂质过氧化和蛋白质硝化的增加。我们假设 LPDA 和 RNS 产量的增加通过共价结合和/或氧化导致内源性大分子（包括蛋白质）的结构改变，从而导致新抗原的形成。抗原加工后，这些新抗原可以通过刺激 T 和 B 淋巴细胞引发自身免疫反应，最终导致 AD，例如系统性红斑狼疮 (SLE)。该假设将通过四个具体目标进行检验：1）描绘氧化应激与自身免疫之间的联系。这将通过将自身免疫倾向（MRL+/+）和耐药（B6C3F1）小鼠暴露于三氯乙烯（TCE，一种已知会导致脂质过氧化/RNS的环境化学物质）来实现。 LPDA-蛋白加合物（在肝、肾和脾中）及其相应抗体的形成将与自身免疫反应相关。通过铁超载、N-乙酰半胱氨酸给药和使用 CYP2E1 敲除 MRL +/+ 小鼠，将进一步确定氧化应激在自身免疫中的作用； 2) 确定TCE诱导的RNS在自身免疫中的作用。使用 iNOS 抑制剂和 iNOS 敲除 MRL +/+ 小鼠，我们将评估 RNS 导致自身免疫的潜力； 3）阐明脂质过氧化引起的自身免疫的机制。利用 LPDA 蛋白加合物，将阐明 T 细胞在自身免疫中的作用； 4) 定义 SLE 患者血清中的氧化/亚硝化应激特征。使用 SLE 患者的血清，将建立氧化应激标记物与疾病进展之间的联系。我们的研究应将氧化应激确定为 AD 的致病机制，并通过疾病标志物的开发为临床干预和医学监测开辟重要途径，并为基于机制的风险评估提供途径。与公共卫生的相关性：自身免疫性疾病是原因不明的严重病理状况。我们的目标是阐明氧化和亚硝化应激在此类疾病发展中的作用。这项研究的结果将为此类疾病的预防和管理提供重要的见解。