This is a research plan to investigate whether peripheral neuropathy, observed in Hashimoto's thyroiditis patients and papillary carcinoma patients, is caused by autoantibodies specific for the extracellular domain of the c-RET tyrosine kinase receptor. c-RET autoantibodies are produced as a result of ectopic expression of c-RET in the thyroid during chronic autoimmune disease. Since c-RET is naturally expressed in enteric neurons and neuromuscular junctions, these autoantibodies may cause aberrant c-RET signaling in neurons, which results in clinical symptoms of chronic thyroid disease, such as slow transit constipation and muscle weakness. The hypothesis being tested here is that autoantibodies bind to RET present on enteric and motor neurons to cause blocking or ligand-independent activation of the receptor.
The specific aims of this proposal are: 1) Correlate the presence of anti-RET antibodies and gastrointestinal dysfunction or muscle weakness in patients with Hashimoto's thyroiditis. In this aim I will sample serum from patients with thyroiditis and assess the reactivity to RET. The titers of anti-RET antibodies will be assessed and used to predict the presence and extent of enteric or neuromuscular deficiency in selected patients. 2) Determine RET receptor signaling in neuronal cells following RET-specific antibody binding. A. Elucidate signaling pathways that are effected by RET autoantibody in vitro. B. Measure the physiological effects of purified RET autoAb on primary enteric neuroblasts. The studies outlined in these aims will aid in understanding the appearance of peripheral neuropathies not explained by other models. The specific relevance to the NINDS is that this is a proposal to investigate how the immune system contributes to peripheral nerve damage. This research will aid in understanding the persistence of constipation and muscle weakness in autoimmune thyroiditis patients even after treatment with hormone replacement such as thyroxine. This proposal is investigating whether gastrointestinal or muscle symptoms exhibited by Hashimoto's thyroiditis or papillary carcinoma patients are caused by immune-mediated process rather than a thyroid dependent mechanism.
| Wixted, Josephine H F; Rothstein, Jay L; Eisenlohr, Laurence C (2012) Identification of functionally distinct TRAF proinflammatory and phosphatidylinositol 3-kinase/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (PI3K/MEK) transforming activities emanating from RET/PTC fusion oncoprotein. J Biol Chem 287:3691-703 |
