The basis of autoimmune thyroid disease remains unclear. Apoptosis, the process responsible for thyroid cell death in thyroiditis, has recently been found to be important in the pathogenesis of this disorder. Work from our laboratory and from others indicates that apoptosis is closely regulated in thyroid cells. We have further shown that unique combinations of inflammatory cytokines facilitate the induction of immune-mediated apoptosis in a manner that can permit thyrocyte destruction and the development of hypothyroidism. Based on these findings, we hypothesize that autoimmune inflammation alters the regulation of programmed cell death in thyroid cells leading to destructive thyroiditis and hypothyroidism. Altered apoptosis could contribute to the pathogenesis of thyroiditis either by facilitating immune-mediated apoptosis of thyrocytes or by allowing neighboring thyroid cells to kill each other (fratricide) with this process eventually depleting thyrocytes to cause hypothyroidism. The studies outlined in this proposal seek to examine this hypothesis in four specific aims. The first specific aim will finish documenting the expression and function of regulated proteins that are involved in specific cell-death pathways in thyroid follicular cells. These molecules include pro and anti-apoptotic regulators involved with either specific death receptors or mitochondrial apoptotic pathways. The second specific aim will identify when and to what degree alterations in the regulation of the apoptotic pathways are present in vivo in thyroid cells, as well as alterations in apoptotic regulatory protein trafficking or processing, particularly during the expression of autoimmune disease. The third specific aim will employ animal models to verify that regulatory changes in the cell death pathways lead to thyroid destruction in autoimmune disease. These studies will clarify how thyroid cells are damaged by autoimmune responses and provide new approaches for predicting individuals at risk and developing therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037141-10
Application #
6887371
Study Section
Endocrinology Study Section (END)
Program Officer
Johnson, David R
Project Start
1995-01-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
10
Fiscal Year
2005
Total Cost
$354,424
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Wang, Su He; Fan, Yongyi; Makidon, Paul E et al. (2012) Induction of immune tolerance in mice with a novel mucosal nanoemulsion adjuvant and self-antigen. Nanomedicine (Lond) 7:867-76
Wang, Su He; Chen, Gwo-Hsiao; Fan, Yongyi et al. (2009) Tumor necrosis factor-related apoptosis-inducing ligand inhibits experimental autoimmune thyroiditis by the expansion of CD4+CD25+ regulatory T cells. Endocrinology 150:2000-7
Wang, Su He; Shi, Xiangyang; Chen, Xisui et al. (2009) Therapeutic efficacy of 2-methoxyestradiol microcrystals encapsulated within polyelectrolyte multilayers. Macromol Biosci 9:429-36
Wang, Su He; Van Antwerp, Mary; Kuick, Rork et al. (2007) Microarray analysis of cytokine activation of apoptosis pathways in the thyroid. Endocrinology 148:4844-52
Wang, Su He; Arscott, Patricia; Wu, Peiqing et al. (2006) No apparent damage in the thyroid of transgenic mice expressing antiapoptotic FLIP. Thyroid 16:1-8
Wang, Su He; Cao, Zhengyi; Wolf, Julie M et al. (2005) Death ligand tumor necrosis factor-related apoptosis-inducing ligand inhibits experimental autoimmune thyroiditis. Endocrinology 146:4721-6
Wang, Su He; Bretz, James D; Phelps, Ellen et al. (2002) A unique combination of inflammatory cytokines enhances apoptosis of thyroid follicular cells and transforms nondestructive to destructive thyroiditis in experimental autoimmune thyroiditis. J Immunol 168:2470-4
Bretz, J D; Baker Jr, J R (2001) Apoptosis and autoimmune thyroid disease: following a TRAIL to thyroid destruction? Clin Endocrinol (Oxf) 55:1-11
Wang, S H; Phelps, E; Utsugi, S et al. (2001) Susceptibility of thyroid cancer cells to 7-hydroxystaurosporine-induced apoptosis correlates with Bcl-2 protein level. Thyroid 11:725-31
Phelps, E; Wu, P; Bretz, J et al. (2000) Thyroid cell apoptosis. A new understanding of thyroid autoimmunity. Endocrinol Metab Clin North Am 29:375-88, viii

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