Thyrotropin Receptor Auto Antibodies in Graves' Ophthalmopathy

描述（由申请人提供）：我们工作的长期目标是更好地了解格雷夫斯眼病（GO）的发病机制，以帮助开发治疗或预防这种疾病的新方法。本提案的实验室研究目标是确定氧化石墨烯眶前脂肪细胞中促甲状腺激素受体（TSHR）导向的自身抗体（TRAb）刺激脂肪形成的机制。翻译目的是确定利妥昔单抗（一种阻断B细胞活化和分化的药物）是否在氧化石墨烯患者的初步研究中具有治疗益处。我们已经证明，氧化石墨烯患者眼眶组织中的脂肪生成增强，并且TRAb可以刺激氧化石墨烯眼眶前脂肪细胞中的脂肪细胞发育。此外，我们已经证明可溶性卷曲相关蛋白-1 （sFRP-1）在患者眼眶组织标本中的表达升高，并提供证据表明TRAb增强了该蛋白在眶前脂肪细胞中的表达。sFRP-1是一种Wnt信号的抑制剂，在脂肪前细胞中起作用，逆转Wnt诱导的脂肪生成抑制，从而促进脂肪细胞的发育。与TRAb激活甲状腺TSHR并刺激格雷夫斯病中甲状腺激素的过量产生类似，我们假设这些自身抗体激活眶前脂肪细胞上的TSHR以刺激氧化石墨烯中的脂肪生成。本提案的3个具体目的是验证以下假设：1)trab诱导的脂肪形成是通过抑制Wnt信号介导的，来自GO患者的IgG具有类似的功能；2)氧化石墨烯眼眶前脂肪细胞对TRAb的反应不同于其他部位的前脂肪细胞；3)利妥昔单抗治疗严重、活动性氧化石墨烯患者有效。我们将招募30名患者参加一项随机、前瞻性、双盲临床试验，以确定该药物对临床活动评分、特定定量眼参数和健康相关生活质量的影响。我们相信，我们的项目代表了一种新颖的、综合的、转化的方法来研究氧化石墨烯。我们的研究将产生有关疾病发展机制的信息，并将确定一种新的治疗方法的有效性。

DESCRIPTION (provided by applicant): The long term objective of our work is to better understand the pathogenesis of Graves' ophthalmopathy (GO) in order to aid in the development of new approaches to treatment or prevention of this disease. The goal of the laboratory investigations in this proposal is to determine mechanisms involved in the stimulation of adipogenesis by thyrotropin receptor (TSHR)-directed autoantibodies (TRAb) in GO orbital preadipocytes. The translational goal is to determine whether rituximab, an agent that blocks the activation and differentiation of B cells, confers therapeutic benefit in a pilot study of patients with GO. We have shown that adipogenesis is enhanced in orbital tissues from GO patients, and that TRAb act to stimulate fat cell development in GO orbital preadipocytes. Further, we have demonstrated elevated expression of soluble frizzled-related protein-1 (sFRP-1) in patients' orbital tissue specimens, and present evidence that TRAb enhance expression of this protein in their orbital preadipocytes. sFRP-1 is an inhibitor of Wnt signaling that acts in preadipocytes to reverse Wnt-induced inhibition of adipogenesis, thereby enhancing fat cell development. Analogous to TRAb activating thyroidal TSHR and stimulating over-production of thyroid hormone in Graves' disease, we postulate that these autoantibodies activate/TSHR on orbital preadipocytes to stimulate adipogenesis in GO. The 3 specific aims of this proposal are to test the hypotheses that: 1) TRAb-induced adipogenesis is mediated via inhibition of Wnt signaling, and that IgG from GO patients function similarly; 2) GO orbital preadipocytes differ from preadipocytes from other sites in their responses to TRAb; and 3) Rituximab is effective in the treatment of patients with severe, active GO. We will enroll 30 patients in a randomized, prospective, double-blind clinical trial to determine effects of this agent on clinical activity score, specific quantitative ocular parameters, and health-related quality of life. We believe that our program represents a novel, integrated, translational approach to the study of GO. Our studies will yield information concerning mechanisms involved in disease development, and will determine the effectiveness of a novel approach to therapy.