Hyperthyroid Graves'disease (GD) and Graves'Orbitopathy are associated with the development of autoantibodies to the TSH receptor (TSHR-Ab) which act as TSH agonists and activate TSHR signal transduction. The purpose of this application is: 1: To develop our lead small molecule agonists to the TSHR. To do this we will use a chemical modification strategy and examine the signaling pathways of the higher affinity analogs both in vitro (thyroid cells) and in vivo (mice). 2. We will use both a virtual and computational screening strategy and a high throughput assay to identify and characterize additional small molecules stimulating or blocking the TSHR 3. We will continue our studies of neutral TSHR monoclonal antibodies as TSHR modulators by using them in vivo in mice to characterize their influence on thyroid function and thyroid cell apoptosis.. 4. We will characterize human neutral antibodies to the TSHR in patients with Graves'disease and their role in the induction of thyroid cell apoptosis in vitro with a view to their potential as regulators of thyroid function in this disorder. The insight gained from these studies will have tremendous potential in furthering our understanding of the role of the TSHR in Graves'disease and of developing useful receptor regulators with therapeutic potential.
Graves'disease is a leading cause of hyperthyroidism in the US and worldwide. Anti-thyroid drugs have many side effects and new therapeutics are needed. This work is designed to address these clinical deficiencies.
|Ma, Risheng; Minsky, Noga; Morshed, Syed A et al. (2014) Stemness in human thyroid cancers and derived cell lines: the role of asymmetrically dividing cancer stem cells resistant to chemotherapy. J Clin Endocrinol Metab 99:E400-9|
|Davies, Terry F; Ali, M Rejwan; Latif, Rauf (2014) Allosteric modulators hit the TSH receptor. Endocrinology 155:1-5|
|Yin, Xiaoming; Sachidanandam, Ravi; Morshed, Syed et al. (2014) mRNA-Seq reveals novel molecular mechanisms and a robust fingerprint in Graves' disease. J Clin Endocrinol Metab 99:E2076-83|
|Ma, Risheng; Latif, Rauf; Davies, Terry F (2013) Thyroid follicle formation and thyroglobulin expression in multipotent endodermal stem cells. Thyroid 23:385-91|
|Tomer, Yaron; Hasham, Alia; Davies, Terry F et al. (2013) Fine mapping of loci linked to autoimmune thyroid disease identifies novel susceptibility genes. J Clin Endocrinol Metab 98:E144-52|
|Davies, Terry F (2013) Is thyroid transplantation on the distant horizon? Thyroid 23:139-41|
|Morshed, Syed A; Ma, Risheng; Latif, Rauf et al. (2013) How one TSH receptor antibody induces thyrocyte proliferation while another induces apoptosis. J Autoimmun 47:17-24|
|Baliram, Ramkumarie; Latif, Rauf; Berkowitz, Joshua et al. (2011) Thyroid-stimulating hormone induces a Wnt-dependent, feed-forward loop for osteoblastogenesis in embryonic stem cell cultures. Proc Natl Acad Sci U S A 108:16277-82|
|Davies, Terry F; Latif, Rauf; Minsky, Noga C et al. (2011) Clinical review: The emerging cell biology of thyroid stem cells. J Clin Endocrinol Metab 96:2692-702|
|Ma, Risheng; Morshed, Syed; Latif, Rauf et al. (2011) The influence of thyroid-stimulating hormone and thyroid-stimulating hormone receptor antibodies on osteoclastogenesis. Thyroid 21:897-906|
Showing the most recent 10 out of 27 publications