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Graves眼病（GO）的发病机制，以帮助开发治疗或预防该疾病的新方法。本实验室研究的目的是确定GO眼眶前脂肪细胞中促甲状腺激素受体（TSHR）导向自身抗体（TRAb）刺激脂肪形成的机制。翻译的目标是确定是否利妥昔单抗，一个代理，阻止激活和分化的B细胞，赋予治疗的好处，在一个试点研究与GO患者。我们已经表明，脂肪生成是增强在眼眶组织从GO患者，TRAb的作用，以刺激脂肪细胞的发展在GO眼眶前脂肪细胞。此外，我们已经证明了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，并提供了TRAb增强该蛋白在眼眶前脂肪细胞中表达的证据。sFRP-1是Wnt信号传导的抑制剂，其在前脂肪细胞中起作用以逆转Wnt诱导的脂肪生成抑制，从而增强脂肪细胞发育。类似于TRAb激活甲状腺TSHR和刺激Graves病中甲状腺激素的过度产生，我们假设这些自身抗体激活眼眶前脂肪细胞上的/TSHR以刺激GO中的脂肪生成。本提案的3个具体目的是检验以下假设：1）TRAb诱导的脂肪形成是通过抑制Wnt信号传导介导的，并且GO患者的IgG功能相似; 2）GO眼眶前脂肪细胞与其他部位的前脂肪细胞对TRAb的反应不同; 3）利妥昔单抗可有效治疗重度活动性GO患者。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、特定定量眼部参数和健康相关生活质量的影响。我们相信，我们的计划代表了一种新的，综合的，翻译的方法来研究GO。我们的研究将产生有关疾病发展机制的信息，并将确定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.