The hallmark of allergic diseases is the infiltration and accumulation of Th2 and Th17 cells at the sites of inflammation. Thus, today it is becoming clear that understanding the biology of pathogenic Th2 and Th17 cells and ways to manipulate their function for the treatment of allergic airway inflammation are needed, and one innovative and rational approach is to identify common target(s) in Th2 and Th17 cells that are indispensable for their function and also therapeutically accessible. The generation of pathogenic T helper subsets relies upon cytokine stimulation and the subsequent activation of Signal Transducer and Activator of Transcription (STAT) proteins. Recently, it was suggested that the transcription factor STAT1 promotes allergen-induced airway inflammation; however the precise role of STAT1 in asthma pathogenesis has not been addressed yet. Our preliminary data indicates that STAT1 is required for expression of Th2 and Th17 signature cytokines and transcriptional factors, suggesting the pivotal role of STAT1 in Th2 and Th17 cell development and consequently in asthma pathogenesis. In fact, STAT1-deficient mice exhibited reduced asthma development. Importantly, we have developed a peptide-based STAT1 inhibitor which targets STAT1 activity in both mouse and human T cells. One dose of the inhibitor administration significantly diminished the expression of Th2 and Th17-derived cytokines, indicating its future therapeutic applications. Based on these findings, we hypothesize that STAT1 targeting will help to disrupt the pathogenic Th2 and Th17 cell responses and consequently decrease asthma symptoms.
In Aim 1, we propose to determine the cellular and molecular mechanisms whereby STAT1 regulates Th2 and Th17 cell differentiation and plasticity among these subsets by utilizing gene knockdown approaches. We will also employ unique IL-4-GFP and IL-17-RFP reporter mouse models to define the function of STAT1 in Th2, Th17 and Th2/Th17 cell programming in both normal and autoimmune settings.
In Aim2, we will elucidate whether targeting of STAT1 function in proallergic Th2 and Th17 cells by administering STAT1 inhibitors is an essential checkpoint for the prevention and treatment of allergic asthma. The proposed research will provide new significant insight into characterization of molecular mechanisms underlying STAT1 function in Th2 and Th17 cells that may potentially project STAT1 as a novel molecular target for the treatment or prevention of allergic asthma in the patients.
Studies using both mouse and human model systems have provided key evidence on the role of T helper (Th)2 and Th17 cytokines in driving allergic inflammation. The overall objective of this proposal is to identify the novel function of STAT1 in regulation of proallergic Th2 and Th17 cell development and function. The proposed project will provide important systemic insights into Th2 and Th17 lineage commitment and will determine whether targeting of STAT1 function in proallergic Th2 and Th17 cells is an essential checkpoint for the prevention and treatment of allergic asthma.
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