Asthma is gaining prevalence in the U.S. with the greatest increase seen among inner city African Americans and Hispanics. Among other factors, a complex interplay of genetic and environmental factors may play a role in this increase. Patients with allergic asthma manifest airway hyper responsiveness, and some show the hallmarks of a classic TH2 response. This TH2 type response points to a prominent role for these cells and their cytokines in the pathology of this disease. An understanding of the development of these cells will allow us to develop approaches to prevent or decrease the severity of this disease. Our long-range goal is to provide a detailed understanding of TH2 cell development, and the effect of TH2 cells and their cytokines on allergic asthma. In pursuit of that goal, the objective of this application is to determine the role of ITK in T cell subset differentiation and in the development of allergic asthma. The central hypothesis is that ITK regulates"""""""" the development of specific T cell subsets, contributing to the development of allergic asthma. Our rationale is that a better understanding of TI42 cell development will provide us with information needed to rationally design methods to treat diseases such as allergies and asthma. We will test our hypothesis by pursuing the following two specific aims: l) Determine the role of ITK in the development ofT cell subsets, and 2) Determine the role of ITK in the development of allergic asthma. The proposed work is innovative, because we will be taking advantage of recently developed transgenic mice, and expect that our approach will make a significant contribution to understanding the role of ITK in T cell subset development and in the pathology of allergic asthma. This information will have a significant impact on human health, as we expect to provide information on the molecular pathology of asthma, and on potential targets such as ITK that may be used to manipulate specific T cell functions involved in allergy and asthma.
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