This proposal outlines a 5 year career development program for the training of an academic physician-scientist in Pediatric Rheumatology and Immunology. The principal investigator has completed residency training in Pediatrics with subspecialty training in Pediatric Rheumatology/Immunology and will now focus on further development of an independent research program in a closely mentored scientific environment. Dr. Hans Ochs, a recognized leader in the field of primary immunodeficiency disorders, will mentor the principal investigator's scientific development and an advisory committee of highly regarded scientists will also provide ongoing scientific and career guidance. Research will focus on evaluating the structure, function, and gene regulation activity of FOXP3 in human T cells. FOXP3 is a critical regulator of CD4+CD25+ regulatory T cell development. Mutations in FOXP3 cause IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) in humans and the Scurfy phenotype in mice. In each case, affected males develop fatal systemic autoimmune disease. The FOXP3 protein has significant sequence homology to the Forkhead/ Winged-helix family of transcription factors and also contains a C2H2 Zinc finger domain, a leucine zipper domain, and an amino-terminal domain rich in proline. Little is known about gene transcription events initiated by FOXP3 in T cells or about the molecular mechanisms by which FOXP3 regulates gene transcription. This project seeks to address these questions.
The specific aims are I - To validate the relevance of key candidate FOXPS-regulated genes (identified by array analysis) in order to utilize these target genes for the study of FOXP3 function and evaluation of the transcription program in CD4+CD25+ TREG. II - To determine the mechanism(s) by which FOXP3 exerts differential regulation of gene transcription by comparing its effect on distinct model promoters. We will evaluate both a positively regulated promoter and a negatively regulated promoter. Ill -To identify preferred DMA-binding sites for FOXP3 and to use this information to further characterize the structure and function of FOXP3 with specific focus on the DNA binding and transactivation/transrepression domains. FOXP3 mutations that we have identified in a large cohort of patients with IPEX will be used to guide our analysis of FOXP3 protein function. We believe that this research will provide new insights into the basic understanding of autoimmune disease and may identify new targets for therapy. The depth and breadth of resources available through the University of Washington and Children's Hospital to study the immunologic basis of autoimmune and immunodeficiency diseases offers a rich training environment for the development of the principal investigator's research program that will provide the basis for his academic career.
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