Graves' ophthalmopathy (GO) is an autoimmune eye disorder closed associated with Graves' hyperthyroidsim. There is convincing experimental evidence that the orbital fibroblast (including the preadipocyte fibroblast subpopulation) is the target cell in GO. However, the autoantigen against which the immune response is directed is unknown. The thyrotropin receptor (TSHr) is a prime candidate to be the orbital autoantigen because its involvement would help to explain the close clinical and laboratory associations between GO and hyperthyroidism. In recent studies, the PI has demonstrated the present of TSHr mRNA and protein in orbital adipose/connective tissues from patients with GO, wile TSHr expression was not apparent in normal orbital tissues. In addition, she showed that orbital preadipocyte fibroblasts, cells lacking fucntional TSHr, can be differentiated in vitro into mature TSHr-bearing adipocytes. These and other findings led to hypothesize that: 1)expression of TSHr in the orbit in GO is linked to the induction of adipogenesis in orbital preadipocyte fibroblasts, and that; 2) the adipocyte TSHr is the orbital autoantigen recognized by orbital-infiltrating lymphocytes in GO. The PI plans to examine these hypotheses using our system of cultured orbital preadipocyte fibroblasts derived from pateints with GO.
In specific aim I, she will define the fibroblast-like cells present in the orbit in GO and identify factors that modulate adipogenesis in these cells. Experiments in Aim II are designed to characterize the obital TSHr and to clarify the link between TSHr expression and adipogenesis in the orbi.
In Aim III, she will determine whether cloned orbital-infiltrating lymphocytes from patients with GO recognize TSHr, or other antigens that are processed """"""""naturally"""""""" by autologous antigen-presenting cells. The main goal of the research program is to increase understanding of the orbital immune response in GO in order that novel and more specific therapeutic and preventive strategies for this condition might be developed.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY008819-13S1
Application #
6953987
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Hunter, Chyren
Project Start
1991-08-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2005-07-31
Support Year
13
Fiscal Year
2004
Total Cost
$270,527
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Kumar, Seema; Leontovich, Alexey; Coenen, Michael J et al. (2005) Gene expression profiling of orbital adipose tissue from patients with Graves' ophthalmopathy: a potential role for secreted frizzled-related protein-1 in orbital adipogenesis. J Clin Endocrinol Metab 90:4730-5
Kumar, Seema; Coenen, Michael J; Scherer, Philipp E et al. (2004) Evidence for enhanced adipogenesis in the orbits of patients with Graves' ophthalmopathy. J Clin Endocrinol Metab 89:930-5
Prabhakar, Bellur S; Bahn, Rebecca S; Smith, Terry J (2003) Current perspective on the pathogenesis of Graves' disease and ophthalmopathy. Endocr Rev 24:802-35
Kumar, Seema; Bahn, Rebecca S (2003) Relative overexpression of macrophage-derived cytokines in orbital adipose tissue from patients with graves' ophthalmopathy. J Clin Endocrinol Metab 88:4246-50
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Jyonouchi, S C; Valyasevi, R W; Harteneck, D A et al. (2001) Interleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves' ophthalmopathy. Thyroid 11:929-34
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Valyasevi, R W; Jyonouchi, S C; Dutton, C M et al. (2001) Effect of tumor necrosis factor-alpha, interferon-gamma, and transforming growth factor-beta on adipogenesis and expression of thyrotropin receptor in human orbital preadipocyte fibroblasts. J Clin Endocrinol Metab 86:903-8
Valyasevi, R W; Erickson, D Z; Harteneck, D A et al. (1999) Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor. J Clin Endocrinol Metab 84:2557-62

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