? Fibroblast activation plays an important role in initiating the inflammatory response. Phenotypic attributes of fibroblasts from specific anatomic regions are thought to underlie the peculiar pattern of manifestations associated with certain disease. Other fibroblast characteristics appear global, such as the expression of chemoattractants including IL-16, a CD4-specific ligand and RANTES, a C-C chemokine. We have found that fibroblasts from patients with Graves' disease (GD), when treated with their IgGs (GD-IgG), become activated and express high levels of IL-16 and RANTES. Control fibroblasts from donors without autoimmune disease fail to respond to these IgGs. GD-IgG which are disease specific, appear to be binding to the insulin-like growth factor 1 receptor (IGF-1R) displayed on fibroblasts. We hypothesize that IGF-1R represents an important activational self-antigen. We now propose the following studies to test our central hypothesis. 1) To define the mechanism(s) involved in the GD-specific anti IGF-1R IgG upregulation of IL-16 and RANTES expression by fibroblasts; 2) To determine the serum levels of GD-IgG, IL-16 and RANTES in autoimmune graves disease patients and normal controls and determine the clinical utility of these parameters; 3) To test in vivo the hypothesis that IGF-1R is a critical self-antigen in GD that when ligated with GD-IgG, activates IL-16 and RANTES expression and T cell infiltration. The candidate and mentor have worked closely together for the last year in a productive relationship. The research career development award, continued mentoring and the availability of the General Clinical Research Center, will allow the candidate to further investigate and answer these clinically relevant questions. The candidate will develop the scientific knowledge base, problem solving abilities and technical skills to develop into an independent researcher. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23EY016339-05
Application #
7490434
Study Section
Special Emphasis Panel (ZRR1-CR-3 (01))
Program Officer
Wujek, Jerome R
Project Start
2004-09-27
Project End
2009-06-30
Budget Start
2008-09-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2008
Total Cost
$179,320
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Chen, Hong; Shan, Shannon J C; Mester, Tünde et al. (2015) TSH-Mediated TNF? Production in Human Fibrocytes Is Inhibited by Teprotumumab, an IGF-1R Antagonist. PLoS One 10:e0130322
Stein, Joshua D; Childers, David; Gupta, Shivani et al. (2015) Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease. JAMA Ophthalmol 133:290-6
Douglas, Raymond S; Mester, Tünde; Ginter, Anna et al. (2014) Thyrotropin receptor and CD40 mediate interleukin-8 expression in fibrocytes: implications for thyroid-associated ophthalmopathy (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 112:26-37
Gillespie, Erin F; Papageorgiou, Konstantinos I; Fernando, Roshini et al. (2012) Increased expression of TSH receptor by fibrocytes in thyroid-associated ophthalmopathy leads to chemokine production. J Clin Endocrinol Metab 97:E740-6
Gillespie, Erin F; Raychaudhuri, Nupur; Papageorgiou, Konstantinos I et al. (2012) Interleukin-6 production in CD40-engaged fibrocytes in thyroid-associated ophthalmopathy: involvement of Akt and NF-?B. Invest Ophthalmol Vis Sci 53:7746-53
Smith, Terry J; Hegedus, Laszlo; Douglas, Raymond S (2012) Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves' orbitopathy. Best Pract Res Clin Endocrinol Metab 26:291-302
Hegedus, Laszlo; Smith, Terry J; Douglas, Raymond S et al. (2011) Targeted biological therapies for Graves' disease and thyroid-associated ophthalmopathy. Focus on B-cell depletion with Rituximab. Clin Endocrinol (Oxf) 74:1-8
Smith, Terry J; Padovani-Claudio, Dolly A; Lu, Ying et al. (2011) Fibroblasts expressing the thyrotropin receptor overarch thyroid and orbit in Graves' disease. J Clin Endocrinol Metab 96:3827-37
Naik, Vibhavari M; Naik, Milind N; Goldberg, Robert A et al. (2010) Immunopathogenesis of thyroid eye disease: emerging paradigms. Surv Ophthalmol 55:215-26
Douglas, Raymond S; Afifiyan, Nikoo F; Hwang, Catherine J et al. (2010) Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 95:430-8

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