Cross-Talk Between Estrogen and T Cells Mediated Pathways in Lupus Pathogenesis

雌激素和 T 细胞之间的交互作用介导狼疮发病机制

• 批准号: 7843484
• 负责人: ALESSANDRA B PERNIS
• 金额: $ 43.79万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843484
• 关键词: Affect; Autoantibodies; B-Lymphocytes; Binding; Binding Proteins; Breast; Cell physiology; Cells; Defect; Development; Disease; Down-Regulation; Elements; Employee Strikes; Epithelial Cells; Epithelium; Estrogens; Event; Exhibits; Family; Feedback; Female; Functional disorder; GTP Phosphohydrolase Activators; Gender; Gene Expression; Genes; Glomerulonephritis; Goals; Gonadal Steroid Hormones; Homeostasis; Hormonal; Human; Hypergammaglobulinemia; Immune; Immunoglobulin G; Laboratories; Lupus; Lymphoid Cell; Mammary gland; Mediating; Modeling; Molecular; Molecular Target; Mus; Pathogenesis; Pathway interactions; Phosphotransferases; Principal Investigator; Production; Promoter Regions; Proteinuria; Recruitment Activity; Regulation; Role; Sex Bias; Signal Transduction; Syndrome; Systemic Lupus Erythematosus; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Transactivation; Transfection; Woman; immunological synapse; lead-binding proteins; lupus-like; member; non-genomic; novel; programs; promoter; protein expression; rho; rho GTP-Binding Proteins; src-Family Kinases

Defects in the appropriate regulation of T cell function and homeostasis are fundamental to the pathogenesis of Systemic Lupus Erythematosus (SLE). Classically, SLE exhibits a striking gender bias and preferentially affects women. Although sex hormones, in particular estrogen, have been shown to affect the development and function of T cells, the molecular pathways by which the hormonal milieu modulates T cell responses are largely unknown. Our laboratory has cloned a novel molecule, termed IBP, which is highly expressed in T cells and is a novel member of a unique family of Rho GTPase activators, which is activated upon TCR engagement. Our studies in mice deficient for IBP have revealed that lack of IBP leads to the development of a lupus-like syndrome characterized by the accumulation of effector T cells and IgG+ B cells, profound hypergammaglobulinemia, autoantibody production, proteinuria and glomerulonephritis. Like human SLE, development of these manifestations primarily affects the female gender. Although IBP is highly expressed in lymphoid cells, IBP can also be found in epithelial cells from the mammary gland and our studies indicate that its expression in both breast epithelium and immune cells can be regulated by estrogen. Furthermore, we have recently found that expression of ERa is downregulated upon T cell stimulation in wt T cells but not in IBP deficient T cells. Taken all together these findings have led us to hypothesize that IBP is an estrogen regulated gene that controls a regulatory feedback loop aimed at restricting estrogen signaling during the activation of T cells. The major goal of this proposal is to dissect the cross-talk between IBP and sex hormones and determine whether IBP can be utilized as a novel molecular target to understand, at a mechanistic level, how sex hormones affect T cell physiology and pathophysiology. Specifically, we will: 1. Assess the mechanisms by which IBP controls the expression of ERa in T cells. 2. Investigate the role of estrogen on the lupus-like syndrome that develops in the absence of IBP.

T细胞功能和稳态的适当调节缺陷是系统性红斑狼疮（SLE）发病的基础。典型地，SLE表现出显著的性别偏见，并且优先影响女性。虽然性激素，特别是雌激素，已被证明会影响T细胞的发育和功能，但T细胞的分子途径， 激素环境调节T细胞应答的机制在很大程度上是未知的。我们的实验室已经克隆了一种新的分子，称为IBP，它在T细胞中高度表达，是一个独特的Rho GT3激活剂家族的新成员，它在TCR接合时被激活。我们在有创血压缺陷的小鼠中的研究表明，缺乏有创血压会导致狼疮样综合征的发展，其特征是效应T细胞的积累， IgG+ B细胞、重度高丙种球蛋白血症、自身抗体产生、蛋白尿和肾小球肾炎。与人类SLE一样，这些表现的发展主要影响女性。虽然IBP在淋巴细胞中高度表达，但也可以在乳腺上皮细胞中发现IBP，并且我们的研究表明其在乳腺上皮和免疫细胞中的表达可以受雌激素调节。此外，我们最近发现，ER α的表达下调后，T细胞刺激野生型T细胞，但不是在IBP缺陷型T细胞。综上所述，这些发现使我们假设IBP是一种雌激素调节基因，其控制调节反馈回路，旨在限制T细胞活化期间的雌激素信号传导。该提案的主要目标是剖析IBP和性激素之间的相互作用，并确定IBP是否可以作为一种新的分子靶点，以了解性激素如何影响T细胞生理学和病理生理学。具体来说，我们将：1。评估IBP控制T细胞中ER α表达的机制。2.研究雌激素在没有IBP的狼疮样综合征中的作用。