Thyrotropin Receptor Autoantibodies in Graves' Ophthalmopathy

项目总结/摘要 我们的主要目标是确定新的和有效的方法来预防和 治疗Graves眼病（GO），与Graves眼病相关的眼病 甲状腺机能亢进GO轨道内的历史变化是惊人的，包括 透明质酸（HA）蓄积和水肿，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 建立，最多可以通过手术干预不完全逆转或调节， 积极的免疫疗法我们对GO的发病机制和临床表现进行了研究， 在过去的二十年里，人们对细胞和分子机制有了新的认识， 这是眼部组织变化的根本原因我们的实验室最近 建立了促甲状腺激素受体（TSHR）自身抗体在这些启动中的作用， 变化我们现在准备大大增加这项工作的重要性和影响。的 需要检验的中心假设是，针对GO轨道TSHR的自身抗体 成纤维细胞启动并维持这些细胞中的疾病过程， 该受体的配体拮抗剂可以抑制这些作用。此外，我们建议， 可以使用新的方法来鉴定处于GO发展或进展的高风险的患者， 生物标志物以及使用目前可获得的甲状腺功能亢进患者的前瞻性研究 临床数据。在本申请中，我们将扩大我们的研究有关的机制， 通过GO中的刺激性、中性和阻断性自身抗体激活TSHR（目的1）。在 此外，我们将确定药物样小分子配体拮抗剂的TSHR的能力， 阻断眼眶成纤维细胞中的受体活化、HA合成和脂肪生成。这些研究 将阐明这些化合物作为新疗法的潜在效用。在目标2中，我们将确定 疾病活动的新生物标志物，将来可能用于识别高风险患者。在 目标3，我们将开发一个临床预测工具，以确定在前瞻性的风险患者， 使用现有患者数据进行研究。可靠地识别高风险患者的能力 对于GO发作或进展将对疾病产生重大影响，因为这些患者 将从旨在防止组织重塑的新疗法中获益最多 具有已确诊疾病的特征。 PHS 398/2590（Rev.06/09）

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