Our long-term objective is to test the hypothesis that poly(ADP-ribose) polymerase-1 (PARP-1) plays an important role in the pathogenesis of allergen-induced respiratory diseases such as asthma, and to promote PARP- 1 as a viable therapeutic target. Asthma is, in part, a Th2 lymphocyte-mediated inflammatory airway disease characterized by pulmonary eosinophilia and airway hyper-responsiveness (AHR). In recent years a great deal of knowledge has accrued about the initiating factors of airway inflammation, identifying Th2 cytokines such as IL-4, IL-5, and IL-13 as major contributors to the process. PARP-1 plays an important role in tissue injury in conditions associated with oxidative stress and inflammation. During the last funding period, our laboratory provided strong evidence for the participation of PARP-1 in the pathogenesis of asthma-associated airway inflammation and AHR. We also demonstrated that post-challenge inhibition of PARP-1 by a drug, TIQ-A, may offer therapeutic potential for treatment of allergic airway inflammation because it blocked eosinophilia, production of Th2 cytokines, mucus production, and AHR. We have accumulated important evidence on the mechanisms by which PARP-1 regulates the expression of important inflammatory genes that critically depend on the transcription factor NF-?B, further supporting our efforts to identify PARP-1 not only as an NAD-utilizing enzyme, but also as an important regulator of inflammatory gene expression. The findings that PARP-1 inhibition, pharmacologically or by gene knockout, was associated with a drastic reduction in Th2 cytokine production (e.g. IL-5) in OVA-challenged mice 2, 27 may be linked to a number of causes that include defects in sensitization, in the generation of Th2 cells, in the recruitment of Th2 cells to the lungs, in cytokine expression, or in a combination of two or more of these defects. In this renewal application, we continue our efforts to decipher the exact mechanisms by which PARP-1 contributes to the pathogenesis of asthma. We will perform the proposed studies using an integrated approach that includes a mouse model, adoptive transfer, a primary cell culture system, viral vectors, and state of the art technology.
Aim 1 Will determine the specific role of PARP-1 in CD4+ Th2 cells-associated manifestation of eosinophilia and IL-5 production in response to allergen exposure.
Aim 2 will determine the mechanism(s) by which PARP-1 affects the nuclear export system that governs NF-?B nuclear localization and ultimate activation of its target genes during inflammation. Relevance to public: Successful completion of these studies will not only provide stronger support for the role of PARP-1 in the pathogenesis of asthma but will also provide clear future venues for our ultimate goal, which is to unravel the intricate processes of allergic inflammation and the potential mechanisms by which PARP-1 participates in this process. These studies will also further support our efforts to establish PARP-1 as a viable target for the therapeutic modulation of airway inflammation and AHR. Thus, this work provides a basis for the development of new and improved approaches to treat asthma and lung diseases that involve oxidant stress and PARP-1 activation.
Our long-term objective is to establish the role of poly(ADP-ribose) polymerase-1 (PARP-1) in the pathogenesis of allergen-induced respiratory diseases such as asthma and to develop treatment strategies based on inhibiting this enzyme for asthma. Allergic asthma ranks among the most common chronic diseases in the United States affecting approximately 20 million individuals and more than 100 million people worldwide. These studies will provide important insight into the poorly understood cellular and molecular mechanisms that underlie asthma and further support our efforts to establish PARP-1 as a viable target for the therapeutic modulation of airway inflammation and its critical consequences such as airway remodeling.
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