Autoimmune Polyendocrinopathy Ectodermal Dystrophy (APECED) is an autosomal recessively inherited autoimmune disorder. The culprit gene, termed Autolmmune Regulator (AIRE), for this syndrome was recently positionally cloned and has afforded a unique opportunity to study the mechanism by which defects in this gene lead to autoimmunity. Preliminary studies have indicated that the gene is primarily expressed in the medulla of the thymus in a unique subset of epithelial cells in this compartment. The hypothesis of this proposal is that the AIRE gene influences the selection of T cells in the thymus and a defect in this gene leads to the autoimmunity seen in APECED patients. There are three major aims of this work. The first is to develop an animal model of APECED by knocking out the gene in mice and to characterize these mice.
A second aim i s to examine how the AIRE gene influences T cell selection in the thymus.
The final aim i s to examine the effects of genetic background and environment on the phenotype of APECED. The candidate in this proposal is a clinical endocrinology fellow with expertise in the general field of immunology. The candidate's goals are to develop a research project that utilizes skills in both fields and expands his knowledge in both fields to position himself for scientific independence. The candidate's long term goal is to run an independent laboratory in an academic setting where 90 percent of his time is devoted to the laboratory and 10 percent of his time is devoted to teaching and clinical work. The laboratory that the proposed work will occur in has a well-established track record in the field of immune tolerance and autoimmunity and will provide an excellent environment for the candidate to pursue these studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08DK059958-03
Application #
6949472
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2002-09-01
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$125,010
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Waterfield, Michael; Khan, Imran S; Cortez, Jessica T et al. (2014) The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat Immunol 15:258-65
Gardner, James M; Metzger, Todd C; McMahon, Eileen J et al. (2013) Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4? T cells. Immunity 39:560-72
Metzger, Todd C; Khan, Imran S; Gardner, James M et al. (2013) Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. Cell Rep 5:166-79
Cheng, Mickie H; Fan, Una; Grewal, Navdeep et al. (2010) Acquired autoimmune polyglandular syndrome, thymoma, and an AIRE defect. N Engl J Med 362:764-6
Shum, Anthony K; DeVoss, Jason; Tan, Catherine L et al. (2009) Identification of an autoantigen demonstrates a link between interstitial lung disease and a defect in central tolerance. Sci Transl Med 1:9ra20
Zhang, Li; Barker, Jennifer M; Babu, Sunanda et al. (2007) A robust immunoassay for anti-interferon autoantibodies that is highly specific for patients with autoimmune polyglandular syndrome type 1. Clin Immunol 125:131-7
Cheng, Mickie H; Shum, Anthony K; Anderson, Mark S (2007) What's new in the Aire? Trends Immunol 28:321-7
DeVoss, Jason J; Anderson, Mark S (2007) Lessons on immune tolerance from the monogenic disease APS1. Curr Opin Genet Dev 17:193-200
DeVoss, Jason; Hou, Yafei; Johannes, Kellsey et al. (2006) Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J Exp Med 203:2727-35
Anderson, Mark S; Venanzi, Emily S; Chen, Zhibin et al. (2005) The cellular mechanism of Aire control of T cell tolerance. Immunity 23:227-39

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