Thyrotropin Receptor Autoantibodies in Graves' Ophthalmopathy

项目摘要/摘要 我们的主要目标是确定新的和有效的方法来预防和 Graves眼病(GO)的治疗--一种与Graves眼病有关的眼病 甲亢。GO轨道内的组织病理学变化是惊人的，包括 透明质酸(HA)积聚和水肿，成熟脂肪细胞数量增加，以及 炎性细胞因子和趋化因子的存在。由此产生的组织重塑，一旦 通过手术干预或调整，充其量只能不完全逆转或调整 积极的免疫疗法。GOVER发病机制及临床表现的研究 在过去的二十年里，人们对细胞和分子机制有了新的见解。 在这种疾病中所见的眼组织变化的潜在原因。我们的实验室最近进行了 确定促甲状腺激素受体(TSHR)自身抗体在这些疾病的启动中的作用 改变。我们现在准备大大提高这项工作的意义和影响。这个 有待检验的中心假设是针对GO轨道上的TSHR的自身抗体 成纤维细胞在这些细胞和小分子中启动和维持疾病过程 该受体的配体拮抗剂可以抑制这些效应。此外，我们建议， 使用新的技术可以识别高危的GO患者。 目前可获得的甲亢患者生物标志物和前瞻性研究 临床数据。在这一应用中，我们将扩大我们对所涉及的机制的研究 在刺激性、中性和封闭的GO自身抗体激活TSHR中(目标1)。在……里面 此外，我们还将测定TSHR的类药物小分子配体拮抗剂的能力 阻断眼眶成纤维细胞的受体激活、HA合成和成脂作用。这些研究 将阐明这些化合物作为新疗法的潜在用途。在目标2中，我们将确定 未来可能被用来识别高危患者的疾病活动的新生物标记物。在……里面 目的3，我们将开发一种临床预测工具，以前瞻性地识别高危患者。 使用当前可用的患者数据进行研究。能够可靠地识别高危患者 对于GO的发病或进展会对疾病有重大影响，因为这些患者 将从旨在防止组织重塑的新疗法中受益最大 以既定疾病为特征的。 PHS 398/2590(06/09版)页面续格式页面

PROJECT SUMMARY/ABSTRACT Our primary objective is to identify novel and effective approaches to the prevention and treatment of Graves' ophthalmopathy (GO), the ocular disease linked to Graves' hyperthyroidism. Histopathologic changes within the GO orbit are striking and include accumulation of hyaluronic acid (HA) and edema, increased numbers of mature fat cells, and the presence of inflammatory cytokines and chemokines. The resultant tissue remodeling, once established, can at best be imperfectly reversed or modulated through surgical intervention or aggressive immunotherapy. Our studies of the pathogenesis and clinical expressions of GO over the past two decades have led to new insights into the cellular and molecular mechanisms underlying the ocular tissue changes seen in the disease. Our laboratory has recently established a role for thyrotropin receptor (TSHR) autoantibodies in the initiation of these changes. We are now poised to greatly increase the significance and impact of this work. The central hypotheses to be tested are that autoantibodies directed against the TSHR in GO orbital fibroblasts initiate and sustain the disease processes in these cells and that small-molecule ligand antagonists of this receptor can inhibit these effects. In addition, we suggest that patients at high risk for the development or progression of GO can be identified using novel biomarkers and by prospective study of hyperthyroid patients using currently obtainable clinical data. In this application, we will expand our studies concerning mechanisms involved in TSHR activation by stimulatory, neutral and blocking autoantibodies in GO (Aim 1). In addition, we will determine the ability of drug-like small molecule ligand antagonists of TSHR to block receptor activation, HA synthesis and adipogenesis in orbital fibroblasts. These studies will clarify the potential utility of these compounds as novel therapy. In Aim 2, we will identify new biomarkers of disease activity that might in future be used to identify high-risk patients. In Aim 3, we will develop a clinical prediction tool to identify at-risk patients in a prospective study using currently available patient data. The ability to reliably identify patients at high risk for GO onset or progression would have significant impact on the disease as these patients would benefit most from novel therapies aimed at preventing the tissue remodeling characteristic of established disease. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page