The basis of autoimmune thyroid disease remains unclear. Most investigations into the pathogenesis of these disorders have focused on immune abnormalities that might lead to an autoimmune response. However, no unique genetic basis has been identified for the immune response to thyroid autoantigens, and many individuals who demonstrate autoimmune responses to thyroid antigens do not develop autoimmune disease. Apoptosis, the process most likely responsible for thyroid cell death in thyroiditis, is closely regulated. Work from our laboratory indicates that apoptosis is specifically regulated in thyroid follicular cells in several unique ways, and that the induction of immune-mediated apoptosis can be blocked or facilitated in a manner that could alter the induction of cytotoxicity. These finding have led to the hypothesis that the regulation of programmed cell death pathways in the thyroid has a significant role in the development of thyroiditis. Altered apoptosis could contribute to the pathogenesis of thyroiditis either by facilitating initial cellular damage that leads to an immune response or by accelerating immune-mediated apoptosis of thyrocytes that results in hypothyroidism. This proposal seeks to examine this hypothesis with four specific aims. The first specific aim will document the expression and function of proteins that are involved in specific cell-death pathways in thyroid follicular cells. These molecules include receptors and ligands involved in at least four distinct cell death signaling pathways. The second specific aim will examine the regulation of the apoptotic pathways present in thyroid cells, particularly the signaling pathways that potentially mediate immune damage to thyroid cells. The third specific aim involves an examination of regulation of the common apoptotic pathway in thyroid follicular cells, which mediates cell death through CASPASE activation, mitochondrial damage and cleavage of death substrates. The expression and regulation of molecules, such as members of the Bcl-2 family, that modulate this process will be clarified and the role that Vitamin D, estrogen, other steroid hormones, and iodine-induced oxidative stress play in modifying the apoptotic potential of thyroid cells will also be addressed. The fourth specific aim will confirm that the identified alterations in apoptosis can alter the susceptibility of thyroid cells to immune mediated cell death in vivo, first by an examination in thyroid slices and by analyzing the expression of death pathway molecules in thyroid cells derived from normal glands vs. thyroiditis. Animal studies involving treatment with specific hormones that alter apoptosis in the thyroid or transgenic animals will also confirm that alterations in death pathways can change the physiology of normal thyroid cells or alter the pathophysiology of thyroiditis. These studies will help to clarify how thyroid cells can be damaged by autoimmune responses and could provide insights into the physiologic regulation of thyroid cell turnover.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037141-05
Application #
6163700
Study Section
Endocrinology Study Section (END)
Program Officer
Kirshner, Susan
Project Start
1995-01-01
Project End
2004-02-29
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
5
Fiscal Year
2000
Total Cost
$279,345
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
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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