A 5-year training program for the development of a career in academic pulmonary immunobiology is outlined in this proposal. The principal investigator has completed residency in internal medicine at Case Western Reserve University and a fellowship in pulmonary and critical care medicine at the University of Chicago. She is now an Instructor in the Section of Pulmonary and Critical Care, University of Chicago. She will expand upon her scientific skills through a unique program of cellular and molecular immunology. This program will promote command of the application of cellular immunology to the study of basic immune mechanisms of human diseases, such as asthma and allergy. Dr. Anne Sperling will mentor the principal investigators scientific development. She is a well-established investigator in cellular immunology and an outstanding mentor who is committed to the development of the principal investigator into an independent clinician-scientist. Dr. Joe G.N. Garcia, Garcia, the Lowell T. Coggeshall Professor and Chairman of Medicine, an outstanding physician-investigator who has successfully trained many clinician-scientists will serve as the Co-Mentor. He will provide expertise in academic and scientific career development. In addition, an advisory committee of accomplished scientists in immunology, pulmonary physiology and molecular biology will contribute to the scientific and career development. The research focus will be the role of Inducible Costimulator (ICOS) expression levels and its influence on T helper cell type 2 (Th2) differentiation. Recent work in the laboratory has demonstrated that ICOS is a susceptibility gene for allergic sensitization and suggest that the expression of ICOS affects Th2 differentiation and/or Th2 effector function. Thus the overall hypothesis of this proposal is that ICOS expression levels are directly associated with immune outcomes. I find that mice heterozygous for the ICOS gene express less surface ICOS than wild-type mice. My preliminary results demonstrate that ICOS heterozygous mice have less Th2 differentiation and Th2-mediated inflammation in a model of allergic airway disease. In this proposal, I will use ICOS heterozygous mice as a model to understand the mechanisms responsible for ICOS directed Th2 differentiation and Th2-mediated airway inflammation. The goal of this proposal is to further our understanding of the immune responses involved in diseases like asthma and allergy, which affect millions of people in the U.S. and worldwide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI059105-05
Application #
7879403
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2006-07-01
Project End
2010-07-31
Budget Start
2010-06-01
Budget End
2010-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$27,679
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Shilling, Rebecca A; Williams, Jesse W; Perera, Jason et al. (2013) Autoreactive T and B cells induce the development of bronchus-associated lymphoid tissue in the lung. Am J Respir Cell Mol Biol 48:406-14
Wu, Qiang; Gardiner, Gail J; Berry, Elizabeth et al. (2013) ICOS-expressing lymphocytes promote resolution of CD8-mediated lung injury in a mouse model of lung rejection. PLoS One 8:e72955
Moore, Tamson V; Clay, Bryan S; Cannon, Judy L et al. (2011) Inducible costimulator controls migration of T cells to the lungs via down-regulation of CCR7 and CD62L. Am J Respir Cell Mol Biol 45:843-50
Shilling, Rebecca A; Wilkes, David S (2011) Role of Th17 cells and IL-17 in lung transplant rejection. Semin Immunopathol 33:129-34
Moore, Tamson V; Clay, Bryan S; Ferreira, Caroline M et al. (2011) Protective effector memory CD4 T cells depend on ICOS for survival. PLoS One 6:e16529
Benson, Heather L; Mobashery, Shahriar; Chang, Mayland et al. (2011) Endogenous matrix metalloproteinases 2 and 9 regulate activation of CD4+ and CD8+ T cells. Am J Respir Cell Mol Biol 44:700-8
Tong, Jiankun; Clay, Bryan S; Ferreira, Caroline M et al. (2010) Fas ligand expression on T cells is sufficient to prevent prolonged airway inflammation in a murine model of asthma. Am J Respir Cell Mol Biol 43:342-8
Bhorade, Sangeeta M; Chen, Hong; Molinero, Luciana et al. (2010) Decreased percentage of CD4+FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome. Transplantation 90:540-6
Grossman, Eric J; Shilling, Rebecca A (2009) Bronchiolitis obliterans in lung transplantation: the good, the bad, and the future. Transl Res 153:153-65
Shilling, R A; Wilkes, D S (2009) Immunobiology of chronic lung allograft dysfunction: new insights from the bench and beyond. Am J Transplant 9:1714-8

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