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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077814-04
Application #
7809625
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Spain, Lisa M
Project Start
2007-05-15
Project End
2012-09-17
Budget Start
2010-05-01
Budget End
2012-09-17
Support Year
4
Fiscal Year
2010
Total Cost
$315,667
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Stan, Marius N; Garrity, James A; Carranza Leon, Barbara G et al. (2015) Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J Clin Endocrinol Metab 100:432-41
Kumar, Seema; Coenen, Michael; Iyer, Seethalakshmi et al. (2015) Forkhead Transcription Factor FOXO1 Is Regulated by Both a Stimulatory Thyrotropin Receptor Antibody and Insulin-Like Growth Factor-1 in Orbital Fibroblasts from Patients with Graves' Ophthalmopathy. Thyroid 25:1145-50
Turcu, Adina F; Kumar, Seema; Neumann, Susanne et al. (2013) A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol Metab 98:2153-9
Iyer, Seethalakshmi; Bahn, Rebecca (2012) Immunopathogenesis of Graves' ophthalmopathy: the role of the TSH receptor. Best Pract Res Clin Endocrinol Metab 26:281-9
Neumann, Susanne; Pope, Arthur; Geras-Raaka, Elizabeth et al. (2012) A drug-like antagonist inhibits thyrotropin receptor-mediated stimulation of cAMP production in Graves' orbital fibroblasts. Thyroid 22:839-43
Bahn, Rebecca S (2012) Emerging pharmacotherapy for treatment of Graves' disease. Expert Rev Clin Pharmacol 5:605-7
Kumar, Seema; Iyer, Seethalakshmi; Bauer, Hilary et al. (2012) A stimulatory thyrotropin receptor antibody enhances hyaluronic acid synthesis in graves' orbital fibroblasts: inhibition by an IGF-I receptor blocking antibody. J Clin Endocrinol Metab 97:1681-7
Yin, Xiaoming; Latif, Rauf; Bahn, Rebecca S et al. (2012) Genetic Profiling in Graves' Disease: Further Evidence for Lack of a Distinct Genetic Contribution to Graves' Ophthalmopathy. Thyroid :
Bahn, R S (2012) Autoimmunity and Graves' disease. Clin Pharmacol Ther 91:577-9
Stan, Marius N; Garrity, James A; Bahn, Rebecca S (2012) The evaluation and treatment of graves ophthalmopathy. Med Clin North Am 96:311-28

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