The understanding of autoimmune thyroid diseases, Hashimoto's thyroiditis and Graves disease (GD), remains superficial and current treatment is symptom-oriented. The mediators responsible for the lymphocytic infiltration and inflammation characteristic of autoimmune thyroid glands have not been identified. The long-term objective of this project is to investigate the role of thyroid epithelial cells in the inflammatory response. Here, we propose experiments designed to 1) investigate the pathogenesis of thyroid inflammation 2) identify potential therapeutic targets for interrupting these processes and 3) identify clinical markers of autoimmune thyroid disease activity. Cellular immunology, protein chemistry and molecular biology techniques will be utilized to examine thyrocyte expression of immunomodulatory molecules in vitro and in situ. We propose to measure serum levels of inflammatory mediators and attempt to correlate their serum levels with disease activity in a 48-month prospective study of patients with Graves' disease. The candidate and mentor have worked closely for over 3 years. This relationship has led to significant production and the generation of supporting preliminary data. With the support of a research career development award, continued mentoring and the availability of a General Clinical Research Center, the candidate will be able to further investigate his findings and answer the clinically relevant questions that have arisen. During the career development period, the candidate will also complete graduate level coursework in molecular biology and translational investigation. The candidate will develop the scientific knowledge base, problem solving abilities, and technical skills which will allow him to develop into a independent physician/scientiist.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23RR017304-03
Application #
6760044
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Wilde, David B
Project Start
2002-07-15
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$133,920
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
Gianoukakis, Andrew G; Leigh, Mary J; Richards, Patrick et al. (2009) Characterization of the anaemia associated with Graves' disease. Clin Endocrinol (Oxf) 70:781-7
Gianoukakis, Andrew G; Smith, Terry J (2008) Recent insights into the pathogenesis and management of thyroid-associated ophthalmopathy. Curr Opin Endocrinol Diabetes Obes 15:446-52
Tsui, Shanli; Naik, Vibha; Hoa, Neil et al. (2008) Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves'disease. J Immunol 181:4397-405
Smith, Terry J; Tsai, Chieh Chih; Shih, Mei-Ju et al. (2008) Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy. Thyroid 18:983-8
Douglas, R S; Gianoukakis, A G; Goldberg, R A et al. (2007) Circulating mononuclear cells from euthyroid patients with thyroid-associated ophthalmopathy exhibit characteristic phenotypes. Clin Exp Immunol 148:64-71
Douglas, Raymond S; Gianoukakis, Andrew G; Kamat, Shweta et al. (2007) Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves'disease may carry functional consequences for disease pathogenesis. J Immunol 178:3281-7
Gianoukakis, Andrew G; Jennings, Timothy A; King, Chris S et al. (2007) Hyaluronan accumulation in thyroid tissue: evidence for contributions from epithelial cells and fibroblasts. Endocrinology 148:54-62
Gilbert, Jacqueline A; Gianoukakis, Andrew G; Salehi, Siamak et al. (2006) Monoclonal pathogenic antibodies to the thyroid-stimulating hormone receptor in Graves' disease with potent thyroid-stimulating activity but differential blocking activity activate multiple signaling pathways. J Immunol 176:5084-92
Gianoukakis, Andrew G; Douglas, Raymond S; King, Chris S et al. (2006) Immunoglobulin G from patients with Graves' disease induces interleukin-16 and RANTES expression in cultured human thyrocytes: a putative mechanism for T-cell infiltration of the thyroid in autoimmune disease. Endocrinology 147:1941-9