The Role of the RET Receptor in Autoimmune Disease

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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.