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.
|Ghonim, Mohamed A; Pyakurel, Kusma; Ju, Jihang et al. (2015) DNA-dependent protein kinase inhibition blocks asthma in mice and modulates human endothelial and CD4? T-cell function without causing severe combined immunodeficiency. J Allergy Clin Immunol 135:425-40|
|Kim, Hogyoung; Abd Elmageed, Zakaria Y; Davis, Christian et al. (2014) Correlation between PDZK1, Cdc37, Akt and breast cancer malignancy: the role of PDZK1 in cell growth through Akt stabilization by increasing and interacting with Cdc37. Mol Med 20:270-9|
|Mukhopadhyay, Partha; Rajesh, Mohanraj; Cao, Zongxian et al. (2014) Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology 59:1998-2009|
|Naura, Amarjit S; Kim, Hogyoung; Ju, Jihang et al. (2013) Minocycline blocks asthma-associated inflammation in part by interfering with the T cell receptor-nuclear factor ýýB-GATA-3-IL-4 axis without a prominent effect on poly(ADP-ribose) polymerase. J Biol Chem 288:1458-68|
|Yadav, Umesh C S; Naura, Amarjit S; Aguilera-Aguirre, Leopoldo et al. (2013) Aldose reductase inhibition prevents allergic airway remodeling through PI3K/AKT/GSK3* pathway in mice. PLoS One 8:e57442|
|Kim, Hogyoung; Abd Elmageed, Zakaria Y; Ju, Jihang et al. (2013) PDZK1 is a novel factor in breast cancer that is indirectly regulated by estrogen through IGF-1R and promotes estrogen-mediated growth. Mol Med 19:253-62|
|Errami, Youssef; Brim, Hassan; Oumouna-Benachour, Karine et al. (2013) ICAD deficiency in human colon cancer and predisposition to colon tumorigenesis: linkage to apoptosis resistance and genomic instability. PLoS One 8:e57871|
|Errami, Youssef; Naura, Amarjit S; Kim, Hogyoung et al. (2013) Apoptotic DNA fragmentation may be a cooperative activity between caspase-activated deoxyribonuclease and the poly(ADP-ribose) polymerase-regulated DNAS1L3, an endoplasmic reticulum-localized endonuclease that translocates to the nucleus during apoptosis. J Biol Chem 288:3460-8|
|Horváth, Béla; Mukhopadhyay, Partha; Kechrid, Malek et al. (2012) ?-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Free Radic Biol Med 52:1325-33|
|Kim, Hogyoung; Naura, Amarjit S; Errami, Youssef et al. (2011) Cordycepin blocks lung injury-associated inflammation and promotes BRCA1-deficient breast cancer cell killing by effectively inhibiting PARP. Mol Med 17:893-900|
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