Trichloroethene Exposure and Autoimmune Hepatitis

三氯乙烯暴露与自身免疫性肝炎

• 批准号: 9333030
• 负责人: M. FIROZE KHAN
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333030
• 关键词: Adoptive Transfer; Age; Albumins; Antigen Presentation; Antinuclear Antibodies; Apoptosis; Apoptotic; Autoantibodies; Autoimmune Diseases; Autoimmune Hepatitis; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biological Markers; CD4 Positive T Lymphocytes; Cells; Chemical Exposure; Chemicals; Chronic; Competence; Data; Dendritic Cells; Development; Disease; Dose; Early Diagnosis; Environment; Environmental Pollution; Exposure to; Foundations; Gene Proteins; Goals; Health; Helper-Inducer T-Lymphocyte; Hepatic; Hepatocyte; Immunize; Immunoglobulin G; Industrialization; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Joints; Kupffer Cells; Link; Liver; Lymphocyte; Lymphocyte Function; Lymphocyte Subset; Mediating; MicroRNAs; Modeling; Modernization; Mus; Nature; Necrosis; Occupational Exposure; Organ; Pathogenesis; Plasma; Pollution; Prevention Research; Prevention strategy; Process; Production; Proteins; Regulation; Research; Role; Sampling; Secondary to; Series; Serum; Symptoms; T-Lymphocyte; Testing; Therapeutic Intervention; Toxic effect; Translational Research; Trichloroethylene; adduct; attenuation; base; cell type; diagnostic biomarker; differential expression; early detection biomarkers; environmental chemical; experimental study; exposed human population; liver inflammation; molecular diagnostics; novel; planetary Atmosphere

Abstract The long-term goal of our research is to elucidate the mechanisms by which environmental chemicals induce chronic inflammation that leads to autoimmune diseases, to develop biomarker(s) for early detection of exposure-related symptoms, to identify targets, and to devise strategies for therapeutic intervention of environment-linked autoimmune hepatitis (AIH). Using autoimmune-prone MRL+/+ mice, we have shown that trichloroethene (TCE), an environmental contaminant and widely used industrial chemical, causes chronic inflammation and AIH. The central hypothesis of this application is that chronic exposure to TCE causes an imbalance between increased apoptosis and reduced clearance of apoptotic bodies due to compromised Kupffer cells, leading to T cell-mediated chronic inflammation of the liver (AIH), and that aberrant regulation of miRNAs contributes to this process. We will test this hypothesis by pursuing three Specific Aims. Aim 1: Our preliminary data from MRL+/+ mice exposed to TCE indicate that progression to liver inflammation, autoimmunity, and AIH is preceded by increased apoptosis and accumulation of apoptotic bodies. Based upon these novel observations, we propose that the delayed clearance of apoptotic bodies contributes to secondary necrosis, leading to inflammation, autoimmunity and ultimately AIH. This will be studied thoroughly by evaluating TCE-mediated apoptosis, clearance of apoptotic bodies, functional competency of Kupffer cells, and characterization of AIH in its progressive development. Aim 2: We have shown that chronic exposure to TCE results in lymphocyte infiltration into the liver. We will now establish the contribution of T and B cells to AIH in TCE-exposed MRL+/+ mouse livers by using a series of depletion and adoptive transfer experiments and functional characterization of lymphocyte subpopulations. To elucidate the key mechanisms of T helper cell activation and autoantibody production, we will investigate functions of hepatic dendritic cells in antigen presentation in the liver following TCE exposure. Aim 3: We have demonstrated a differential expression of mouse liver miRNAs following TCE exposure. To establish their role in TCE-mediated AIH, we will (a) evaluate the expression of relevant miRNAs in hepatocytes, Kupffer cells, and lymphocytes isolated from the liver, and (b) induce/inhibit relevant miRNA(s) in these cells from control and TCE-treated MRL+/+ mice, and correlate the miRNA profile with changes in their downstream targets associated with apoptosis, inflammation and autoimmunity. Furthermore, plasma samples from mice will also be screened for relevant miRNAs, since a differential miRNA profile in the plasma has the potential to serve as a biomarker of AIH. This project will be performed by our existing strong interdisciplinary team and will provide in-depth mechanistic information on how environmental chemicals contribute to chronic inflammatory diseases such as AIH.

抽象的 我们研究的长期目标是阐明环境化学物质诱发的机制 导致自身免疫性疾病的慢性炎症，开发用于早期检测的生物标志物 暴露相关症状，确定目标，并制定治疗干预策略 环境相关自身免疫性肝炎（AIH）。使用具有自身免疫倾向的 MRL+/+ 小鼠，我们已经证明 三氯乙烯 (TCE) 是一种环境污染物和广泛使用的工业化学品，会导致慢性 炎症和 AIH。本申请的中心假设是，长期接触 TCE 会导致 细胞凋亡增加与凋亡小体清除减少之间的不平衡 库普弗细胞受损，导致 T 细胞介导的慢性肝脏炎症 (AIH) miRNA 的异常调控促成了这一过程。我们将通过追求三个来检验这个假设 具体目标。目标 1：我们对暴露于 TCE 的 MRL+/+ 小鼠的初步数据表明，进展为 肝脏炎症、自身免疫和 AIH 之前会出现细胞凋亡增加和细胞凋亡的积累 尸体。基于这些新的观察，我们提出凋亡小体的延迟清除 导致继发性坏死，导致炎症、自身免疫并最终导致 AIH。这将是 通过评估 TCE 介导的细胞凋亡、凋亡小体的清除、功能性 库普弗细胞的能力，以及 AIH 逐步发展的特征。目标2：我们有 研究表明，长期接触 TCE 会导致淋巴细胞浸润到肝脏。我们现在将建立 T 和 B 细胞对 TCE 暴露的 MRL+/+ 小鼠肝脏中 AIH 的贡献 淋巴细胞亚群的过继转移实验和功能表征。为了阐明 T辅助细胞激活和自身抗体产生的关键机制，我们将研究其功能 TCE 暴露后肝树突状细胞在肝脏中呈递抗原。目标3：我们有 证明了暴露于 TCE 后小鼠肝脏 miRNA 的差异表达。确立他们的角色 在 TCE 介导的 AIH 中，我们将 (a) 评估肝细胞、Kupffer 细胞中相关 miRNA 的表达， 和从肝脏分离的淋巴细胞，以及 (b) 诱导/抑制这些对照细胞中的相关 miRNA 和 TCE 处理的 MRL+/+ 小鼠，并将 miRNA 谱与其下游靶标的变化相关联 与细胞凋亡、炎症和自身免疫有关。此外，来自小鼠的血浆样本也将 筛选相关 miRNA，因为血浆中的差异 miRNA 谱有可能作为 AIH 的生物标志物。该项目将由我们现有的强大的跨学科团队执行，并将提供 关于环境化学物质如何导致慢性炎症疾病的深入机制信息 如AIH。