Oxidative Stress and Autoimmunity

氧化应激和自身免疫

基本信息

批准号：
9263612
负责人：
M. FIROZE KHAN
金额：
$ 34.02万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263612
关键词：
Affect Aldehydes Antigens Antioxidants Attenuated Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Cells Chemicals Chronic Data Development Disease Down-Regulation Funding Genetic Transcription Goals Human Immune Impairment Inflammation Inflammation Mediators Inflammatory Inflammatory Response Lead Life Link Lipids Lupus Nephritis Lymphocyte Lymphocyte Activation Mediating Metals Modification NF-kappa B Nitrogen Nuclear Translocation Occupational Organic solvent product Oxidative Stress Oxygen Pathogenesis Pathogenicity Pathologic Pathway interactions Pharmaceutical Preparations Play Poly(ADP-ribose) Polymerases Population Predisposition Preventive Proteins Proteomics Role Sulforaphane Systemic Lupus Erythematosus T-Cell Proliferation Testing Therapeutic Toxic effect Trichloroethylene Work adduct base biological adaptation to stress cytokine design environmental agent environmental chemical lupus-like novel novel therapeutics oxidation prevent response therapeutic development transcription factor translational approach

项目摘要

Abstract Oxidative stress (OS) has been implicated in the pathogenesis of autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), and a large number of environmental chemicals are known to cause OS. Our long-term goal is to elucidate the role of OS in the development of ADs that are induced by environmental chemicals, and use this information to design preventive or therapeutic strategies. Trichloroethene (TCE) has been implicated in causing ADs, including SLE-like diseases in humans. Previously, we have established an association between TCE-mediated OS and autoimmune response/SLE. This competitive continuation application is based on the premise that TCE exposure affects diverse OS-responsive pathways to lead to a pathogenic response. We hypothesize that TCE-induced oxidative stress causes impairment in PARP-1 and Nrf-2 expression, leading to a harmful inflammatory/autoimmune response. Furthermore, lipid-derived reactive aldehydes (LDRAs) cause structural modifications to endogenous proteins, resulting in the formation of neoantigens which, via lymphocyte activation, contribute to ADs. To test our hypothesis, the following specific aims are proposed: Aim 1 will define the role of PARP-1 activation in TCE-mediated autoimmunity/SLE and will test the hypothesis that TCE-induced activation of PARP-1 leads to a pro-inflammatory response and confers higher susceptibility for SLE/autoimmunity. Studies in this aim will establish a clear link between PARP-1 activation and TCE-mediated autoimmunity/SLE, determine that modulation of PARP-1 abrogates TCE- mediated autoimmune response, and examine PARP-1's potential to act as a coactivator of NF-kB-mediated transcription of pro-inflammatory mediators/cytokines. Aim 2 will determine that impaired Nrf2 expression plays a critical role in the pathogenesis of TCE-mediated SLE, and will test the hypothesis that reduced expression of Nrf2 exacerbates the development of TCE-mediated lupus nephritis. Nrf2 activation will likely attenuate inflammation and disease pathogenesis. Studies in this aim will establish that absence of Nrf2 exacerbates TCE-mediated autoimmune response, and also determine that antioxidant sulforaphane (SFN) ameliorates TCE-mediated SLE by upregulating Nrf2. Aim 3 will elucidate that lipid-derived reactive aldehydes (LDRAs) contribute to TCE-mediated SLE, and will test the hypothesis that LDRA modification of endogenous proteins results in the formation of neo-antigens, which by activating lymphocytes can elicit an autoimmune response. We will determine that LDRA-protein adducts aggravate T cell proliferation, especially Th17 cells, and induce inflammatory cytokines. Furthermore, we will characterize LDRA-protein adducts (proteomic approaches) and determine their autoimmune potential. Our studies will firmly establish a role for OS in the induction and/or exacerbation of autoimmunity/SLE, will delineate novel mechanisms of pathogenesis, and will serve as a stepping stone to translational strategies to prevent autoimmune responses to TCE and other chemicals/drugs known to cause toxicity via OS.

抽象的氧化应激 (OS) 与自身免疫性疾病 (AD) 的发病机制有关，包括系统性红斑狼疮 (SLE) 和大量环境化学物质已知会导致 OS。我们的长期目标是阐明 OS 在环境诱导的 AD 发展中的作用化学品，并使用这些信息来设计预防或治疗策略。三氯乙烯 (TCE) 与导致 AD 相关，包括人类的 SLE 类疾病。此前，我们已经建立了一个 TCE 介导的 OS 与自身免疫反应/SLE 之间的关联。这种竞争的延续应用程序基于以下前提：TCE 暴露会影响多种 OS 响应途径，从而导致致病反应。我们假设 TCE 诱导的氧化应激会导致 PARP-1 和 Nrf-2 表达，导致有害的炎症/自身免疫反应。此外，脂质衍生的反应性醛类 (LDRA) 会引起内源性蛋白质的结构修饰，从而形成新抗原通过淋巴细胞激活导致AD。为了检验我们的假设，具体如下提出目标：目标 1 将定义 PARP-1 激活在 TCE 介导的自身免疫/SLE 中的作用，并将检验 TCE 诱导的 PARP-1 激活导致促炎症反应的假设，并赋予系统性红斑狼疮/自身免疫性疾病的易感性较高。针对这一目标的研究将在 PARP-1 之间建立明确的联系激活和 TCE 介导的自身免疫/SLE，确定 PARP-1 的调节消除了 TCE- 介导的自身免疫反应，并检查 PARP-1 作为 NF-kB 介导的共激活剂的潜力促炎介质/细胞因子的转录。目标 2 将确定 Nrf2 表达受损在 TCE 介导的 SLE 发病机制中发挥关键作用，并将检验表达减少的假设 Nrf2 的缺失会加剧 TCE 介导的狼疮性肾炎的发展。 Nrf2 激活可能会减弱炎症和疾病发病机制。针对这一目标的研究将证实 Nrf2 的缺乏会加剧 TCE 介导的自身免疫反应，并确定抗氧化剂萝卜硫素 (SFN) 可以改善 TCE 通过上调 Nrf2 介导 SLE。目标 3 将阐明脂质衍生的反应性醛 (LDRA) 有助于 TCE 介导的 SLE，并将检验 LDRA 修饰内源蛋白的假设导致新抗原的形成，通过激活淋巴细胞可以引发自身免疫反应。我们将确定LDRA蛋白加合物会加剧T细胞增殖，尤其是Th17细胞，并诱导炎症细胞因子。此外，我们将表征 LDRA-蛋白质加合物（蛋白质组学方法）和确定他们的自身免疫潜力。我们的研究将坚定地确立操作系统在诱导和/或自身免疫/系统性红斑狼疮的恶化，将描述新的发病机制，并将作为防止对 TCE 和其他化学品/药物产生自身免疫反应的转化策略的垫脚石已知会通过操作系统引起毒性。