DESCRIPTION (provided by applicant): Inflammatory cell recruitment into the lungs and airway hyperresponsiveness are key components of asthma. The allergen-induced inflammatory response in the lungs results from the interaction of key airway resident cells and inflammatory cells that release local mediators. Airway smooth muscle (ASM) participates in the inflammatory response of the lungs by phenotypic changes that include synthesizing inflammatory mediators as well as an increase in contractility. Although anti-inflammatory agents and beta-adrenergic bronchodilators remain the primary treatment for chronic and acute episodes of bronchoconstriction, there is a great need for newer therapeutic targets that can modify the development and treatment of asthma. For that reason, molecular targets that might be predicted to suppress allergic inflammatory responses as well as bronchoconstriction are highly desirable. Actin dynamics is well established as the primary mechanism for motility and migration for many cell types, including inflammatory cells. Thus, targeting steps involved in actin dynamics might constitute a mechanism for suppressing the recruitment and migration of inflammatory cells into the lungs. Contractile stimulation also causes the polymerization of a pool of actin in (ASM) cells, and actin polymerization must occur in addition to crossbridge cycling for the generation of active tension. Exciting and novel data presented in the proposal also implicates actin dynamics in the direct responses of ASM tissues to inflammatory stimuli. The molecular mechanisms that regulate actin polymerization in ASM are analogous to those described for cell migration; therefore targeting molecular intermediaries common to the regulation of actin dynamics in smooth muscle and inflammatory cells might provide an effective means of suppressing airway responsiveness and inflammation. As p21-activated protein kinases (PAK) are involved in regulation of F-actin dynamics, they may provide a molecular target for the inhibition of both inflammation and ASM contractility. A novel molecular mechanism for the role of Pak in cytoskeletal signaling pathways that mediate both the contractile and inflammatory responses of ASM cells is proposed. Preliminary data support an important role for Pak in modulating the allergic inflammatory responses of ASM in vitro and in a murine model of asthma in vivo. Small molecular PAK inhibitors are currently under development for cancer chemotherapy and may thus become clinically available in the foreseeable future. The hypothesis that PAKs may serve as an ideal target for asthma therapy because they may be directly involved in the regulation of ASM responsiveness as well the inflammatory responses of the lungs and airways will be pursued in 3 Specific Aims to determine: 1) the molecular mechanisms by which Pak regulates the responses of ASM to contractile and inflammatory stimuli; 2) whether targeting an actin regulatory pathway inhibits airway responsiveness, inflammation and remodeling in a murine model of asthma; 3) whether the acute inhibition of PAK activity can prevent the development of airway inflammation and airway remodeling in a murine asthma model.
|Effective start/end date||8/1/13 → 4/30/17|
- National Institutes of Health: $550,822.00
- National Institutes of Health: $542,559.00
- National Institutes of Health: $429,181.00
- National Institutes of Health: $539,805.00