The overall objective of this AADRC Program is to evaluate the cellular and molecular basis for asthma, in order to identify novel strategies for eventual therapeutic intervention. To achieve this goal, four research projects are proposed to address three interrelated facets of the asthmatic process: immune mechanisms that underlie chronic airway inflammation, apoptotic disruption of airway epithelial integrity, and genetic predispositions to atopy and to airway constrictor hyper-responsiveness. The comprehensive, mechanistic evaluations proposed require special expertise in the fields of immunology, cell signaling, molecular biology, and molecular genetics. An important feature of this AADRC proposal is that scientists from outside the traditional pulmonary community join with senior airways investigators to form a cohesive, interactive research program that incorporates a wide range of new perspectives, technologies, and approaches. Project 1, Role of ICOS Expression Level in Atopy, addresses how genetic variations in the human ICOS gene that have been associated with atopy influence ICOS expression levels, and how these in turn modulate T cell function and allergic airway inflammation. Project 2, Role of Lymphotoxin in IgE Deficiency-induced Airway Inflammation, evaluates how reduced IgE levels in lymphotoxin-deficient mice lead to Th1-dominant airway inflammation and structural changes that mimic chronic severe asthma, and prompts the novel idea that a subset of asthmatics may have Th1-dominant, rather than Th2-dominant, airway inflammation. Project 3, Genetic Basis of Airway Hyper-responsiveness, will identify the mutation(s) and physiological mechanisms that have caused native airway cholinergic hyper-responsiveness in recently established kindred of chemically mutagenized mice. Project 4, Role of TGF-B in Protection Against Airway Epithelial Cell Apoptosis in Asthma, tests the molecular mechanisms by which this growth factor protects normal, but not asthmatic, airway epithelium from apoptosis. These projects form a research program whose sum is greater than its parts, for: (i) they follow a logical thematic progression from basic allergic and non-allergic immune mechanisms in airway inflammation, into epithelial barrier function that constitutes the first line of defense against immune activation, and into identification of gene variations responsible for cardinal features of asthma; (ii) they benefit from considerable exchange of expertise and commonality of approach; and (iii) they take advantage of three common core organizations (Mouse Breeding, Human Subject Recruitment, and Administration) that enhance research efficiency and productivity. Data derived from these collaborative studies will yield new insights into the cellular and molecular mechanisms underlying asthma, and therefore should suggest strategies for novel therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI056352-05
Application #
7204126
Study Section
Special Emphasis Panel (ZAI1-GB-I (M1))
Program Officer
Dong, Gang
Project Start
2003-09-01
Project End
2008-08-29
Budget Start
2007-03-01
Budget End
2008-08-29
Support Year
5
Fiscal Year
2007
Total Cost
$1,277,048
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
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Dowell, M L; Lavoie, T L; Lakser, O J et al. (2010) MEK modulates force-fluctuation-induced relengthening of canine tracheal smooth muscle. Eur Respir J 36:630-7
White, S R; Loisel, D A; McConville, J F et al. (2010) Levels of soluble human leukocyte antigen-G are increased in asthmatic airways. Eur Respir J 35:925-7
Clay, Bryan S; Shilling, Rebecca A; Bandukwala, Hozefa S et al. (2009) Inducible costimulator expression regulates the magnitude of Th2-mediated airway inflammation by regulating the number of Th2 cells. PLoS One 4:e7525
Shilling, Rebecca A; Clay, Bryan S; Tesciuba, Amanda G et al. (2009) CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo. Cell Immunol 259:177-84
Tesciuba, Amanda G; Shilling, Rebecca A; Agarwal, Monica D et al. (2008) ICOS costimulation expands Th2 immunity by augmenting migration of lymphocytes to draining lymph nodes. J Immunol 181:1019-24
Lakser, O J; Dowell, M L; Hoyte, F L et al. (2008) Steroids augment relengthening of contracted airway smooth muscle: potential additional mechanism of benefit in asthma. Eur Respir J 32:1224-30
Mitchell, Richard W; Dowell, Maria L; Solway, Julian et al. (2008) Force fluctuation-induced relengthening of acetylcholine-contracted airway smooth muscle. Proc Am Thorac Soc 5:68-72
Pinto, Lawrence H; Eaton, Emily; Chen, Bohao et al. (2008) Gene-environment interactions in a mutant mouse kindred with native airway constrictor hyperresponsiveness. Mamm Genome 19:2-14
Bandukwala, Hozefa S; Clay, Bryan S; Tong, Jiankun et al. (2007) Signaling through Fc gamma RIII is required for optimal T helper type (Th)2 responses and Th2-mediated airway inflammation. J Exp Med 204:1875-89

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