CONSEQUENCES OF THYMIC ATROPHY INDUCED BY TCDD AND E2

TCDD 和 E2 引起的胸腺萎缩的后果

• 批准号: 6030240
• 负责人: ALLEN Edgar SILVERSTONE
• 金额: $ 26.82万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030240
• 关键词: T lymphocyte; apoptosis; aromatic hydrocarbon receptor; atrophy; autoimmune disorder; autoimmunity; cell growth regulation; developmental immunology; dioxins; environmental toxicology; estradiol; estrogen receptors; gene expression; genetically modified animals; hematopoietic stem cells; laboratory mouse; receptor expression; thymectomy; thymus disorder

Estrogens and dioxins induce immunosuppression and thymic atrophy. Estrogens also are associated with autoimmune disease, while dioxin has been shown to be associated with induction of markers of hyper-immunity. The first aims of this application is identification of the precise alteration(s) in intrathymic development that are associated with thymic atrophy induced by the above agents and related compounds, and, by using transgenic mice containing appropriate reporter constructs, to identify the particular intra-thymic hemopoietic or stromal cells in which either the dioxin receptor (AhR) or the estrogen receptors (ER) are activated to affect T-cell development. The specific cellular targets will be confirmed by use of transgenic mice lacking either the AhR or one or both of the defined ERs. Radiation induced hemopoietic chimeras of mice arrested in T- cell development, lacking receptor, and containing receptor reporter constructs, will be used to precisely define the cell target for atrophy. Once these target cells are defined, and the alteration (either proliferation/differentiation arrest or apoptosis) confirmed, the particular gene products produced in these cells by AhR or ER activation will be elucidated. The second aim is to determine whether there is a direct link between premature thymic atrophy induced by TCDD or E2 or DES and the development of autoimmunity, and if so, what is the mechanistic relation between the two processes. Such studies would provide insight into how estrogens contribute to autoimmunity, and what the risk might be of chronic administration of estrogenic compounds and 'environmental' estrogens. Specifically, this proposal seeks to determine what altered T- cell populations in the periphery and thymus contribute to the lupus-like autoimmune nephritis facilitated by E2, DES, and TCDD in the NZB x SWR (SNF/1) murine model. Whether thymic atrophy is essential to disease induction, will be explored by pre and post-exposure thymectomy, as well as by determining the minimal doses needed to induce the pathology associated markers.

雌激素和二恶英会引起免疫抑制和胸腺萎缩。 雌激素也与自身免疫性疾病有关，而二恶英则与自身免疫性疾病有关。 已被证明与过度免疫标志物的诱导有关。 该应用程序的首要目标是识别精确的 与胸腺相关的胸腺内发育的改变 由上述药剂和相关化合物诱导的萎缩，以及通过使用 含有适当报告构建体的转基因小鼠，以鉴定 特定的胸腺内造血细胞或基质细胞，其中 二恶英受体（AhR）或雌激素受体（ER）被激活 影响T细胞发育。具体的细胞目标将被确认 通过使用缺乏 AhR 或其中一种或两种的转基因小鼠 定义的 ER。辐射诱导小鼠造血嵌合体在T-中被捕 细胞发育，缺乏受体，含有受体报告基因 构建体将用于精确定义萎缩的细胞靶点。 一旦定义了这些目标细胞，并且改变（或者 增殖/分化停滞或细胞凋亡）证实， 通过 AhR 或 ER 激活在这些细胞中产生的特定基因产物 将被阐明。第二个目的是确定是否存在 TCDD、E2 或 DES 引起的过早胸腺萎缩之间的直接联系 以及自身免疫的发展，如果是的话，其机制是什么 两个进程之间的关系。此类研究将提供见解 了解雌激素如何促进自身免疫以及可能存在的风险 长期服用雌激素化合物和“环境” 雌激素。具体来说，该提案旨在确定是什么改变了 T- 外周和胸腺中的细胞群有助于狼疮样 NZB x SWR 中 E2、DES 和 TCDD 促进的自身免疫性肾炎 (SNF/1) 小鼠模型。胸腺萎缩是否是疾病所必需的 诱导，也将通过暴露前和暴露后胸腺切除术进行探索 例如通过确定诱发病理所需的最小剂量 相关标记。