STAT signaling in dendritic cells during asthma

Columbia University Health Sciences, New York NY

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Abstract

Description (provided by applicant): Asthma is a prevalent disease that continues to increase at an alarming rate. A more detailed understanding of how imbalances in immune response lead to the development of allergic diseases like asthma will be important in the design of more effective therapeutics. The recent development of murine models of asthma has provided a great opportunity to dissect the inflammatory events that give rise to this debilitating disease. These studies have determined that the polarization of T-helper cells toward the Th2 subset (at the expense of the Th1 subset) is critical in the development of the allergic phenotype. Moreover, the cytokines secreted by Th2 cells mediate most of the inflammatory events associated with asthma. But how does the imbalanced Th2 response arise? Recent studies have suggested that dendritic cells (DCs), which play a vital role in driving the development of naive T-cells into the Th2 (or Th1) subsets, are also important in regulating the balance between Th1 and Th2 cells. Moreover, cytokines secreted by activated T-cells regulate DCs and the polarization process. Thus, these cytokine feedback loops that serve to maintain a balanced immune response, fail during the development of allergic disease. Cytokines transduce their signals through the activation of one or more members of the STAT (Signal Transducers and Activators of Transcription) family of transcription factors. Recently, each of the six STATs genes has been individually targeted for deletion. Characterization of these knockout mice has demonstrated that STAT-dependent signals are both highly specific and pivotal to the biological response of cytokines. These mice provide an opportunity to explore the role of cytokines, and the specific STAT signaling pathways they activate, in the development of DCs and in the ability DCs to promote an imbalanced polarization toward Th2 cells, so important in the pathogenesis of allergic disease. Specifically we propose to: (1) determine whether DCs from STAT knockout mice function normally in vitro; (2) determine whether STAT knockout DCs will be able to promote the development of asthma; and (3) determine whether DCs with constitutively active STATs promote exuberant inflammation.