The Role of the RET Receptor in Autoimmune Disease

描述（由申请人提供）：甲状腺自身免疫性疾病在美国困扰着200多万人，但对这种疾病的病因、如何维持或如何进展知之甚少。因此，甲状腺功能障碍很普遍，并导致大量持续的公共卫生疾病，包括心血管疾病、不孕症、肥胖症以及中枢和外周神经功能障碍。我们研究的长期目标是了解致癌酪氨酸激酶受体c-RET如何介导许多与甲状腺自身免疫性疾病相关的炎症。在形成该提议的基础的工作中，我们发现RET激酶的组成性信号传导可以引发炎症信号传导途径，包括由NFxfi转录复合物触发的那些。这种激活主要负责将产生甲状腺激素的上皮细胞转化为产生细胞因子、趋化因子和相关介质的细胞。最近，我们发现，异位表达的c-RET受体连同抗RET抗体经常出现在患有多结节性甲状腺肿，桥本甲状腺炎和/或分化型甲状腺癌的患者。为了阐明RET激酶激活和自身免疫性疾病之间的联系，我们已经开发了几种新的基于抗RET抗体结合c-RET胞外结构域（RETECD）的体外和体内模型。在该提案中，我们将扩展初步数据并检查抗RETECD抗体交联、激动或阻断c-RET受体功能从而增强或抑制激酶诱导的信号转导的潜力。为了检验这一假设，我们概述了三个目标，指导三个假设的基础上，这个模型。在第一个目标中，我们将直接测试RETECD特异性抗体诱导受体活化和由此产生的炎性细胞因子合成的能力。在第二个目标中，我们将在体外检测来自诊断为自身免疫性疾病或相关甲状腺疾病的甲状腺患者的血清的c-RET结合活性。最后，为了检查抗RETECD抗体结合的病理后果，我们开发了小鼠模型。因此，预测在小鼠中注射抗RETECD抗体会阻断肠神经元上生理表达的c-RET受体，导致细胞凋亡和胃肠功能障碍。在平行实验中，我们提出具有不同特异性的抗RETEdD抗体将激动c-RET * 肿瘤上表达的异位c-RET并引起自身炎症反应。这些研究的结果将更好地了解异位c-RET信号如何增强炎症并导致甲状腺功能障碍和周围神经病变。通过破译RETECD抗体在疾病中的作用，我们可以设计改进的方法和药物来消除甲状腺和其他器官特异性自身免疫性疾病。

DESCRIPTION (provided by applicant): Thyroid autoimmune disease' afflicts over 2 million people in the United States and yet very little is known about what causes this disease, how it is maintained or how it progresses. As a result, thyroid dysfunction is widespread and contributes to a large number of persistent public health maladies including cardiovascular disease, infertility, obesity and central and peripheral neurological dysfunction. The long-term goal of our research has been to understand how an oncogenic tyrosine kinase receptor known as c-RET can mediate many of the inflammatory conditions associated with thyroid autoimmune disease. In work that forms the basis of this proposal, we find that constitutive signaling of the RET kinase can provoke inflammatory signaling pathways including those triggered by the NFxfi transcriptional complex. This activation is largely responsible for transforming thyroid hormone producing epithelial cells into cells producing cytokines, chemokines, and related mediators. More recently, we found that ectopic expression of the c-RET receptor together with anti-RET antibodies appears often in patients afflicted with multinodular goiter, Hashimoto's thyroiditis and/or differentiated thyroid cancer. To elucidate the connection between RET kinase activation and autoimmune disease we have developed several new in vitro and in vivo models based on anti RET antibody binding of the c-RET extracellular domain (RETECD). In this proposal, we will expand on preliminary data and examine the potential for anti-RETECD antibody to cross-link, agonize or block the function of the c- RET receptor thus potentiating or inhibiting kinase-induced signal transduction. To test this hypothesis, we have outlined three aims guiding three hypotheses based on this model. In the first aim, we will directly test the capability of RETECD specific antibody to induce receptor activation and the resulting synthesis of inflammatory cytokines. In the second aim, we will examine serum from thyroid patients diagnosed with autoimmune disease or related thyroid disorders for c-RET binding activity in vitro. Finally, to examine the pathological consequences of anti-RETECD antibody binding, we have developed a mouse model. Accordingly, injection of anti-RETECD antibody in mice is predicted to block c-RET receptors physiologically expressed on enteric neurons leading to apoptosis and gastrointestinal dysfunction. In parallel experiments, we propose that anti-RETEdD antibody with a different specificity will agonize ectopic c-RET expressed on c- RET* tumors and cause an auto-inflammatory response. Results from these studies will provide a better understanding of how ectopic c-RET signaling can potentiate inflammation and lead to thyroid dysfunction and peripheral neuropathies. By deciphering the role of RETECD antibody in disease, we can design improved methods and drugs for the abrogation of thyroid and other organ-specific autoimmune disorders.