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.
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