Severe acute asthma, defined as asthma that is refractory to current anti-inflammatory agents and bronchodilators, accounts for an estimated two-million emergency department visits annually. beta 2-adrenergic receptor agonists (beta-agonists) are widely used for the treatment of bronchospasm associated with acute asthma attacks, however, some patients develop refractory responses to long term usage of beta-agonists, and it also causes adverse effects in patients with a genetic polymorphism (Arg/Arg genotype, about a sixth of the US population) in the adrenergic receptor creating a need for additional therapeutics for managing asthma. Beta-agonists mediate their effect primarily through activation of beta 2 -adrenergic receptor-adenylate cyclase pathway, but the molecular mechanisms underlying the action of beta-agonists are still not completely defined. Recently, we and others have demonstrated that beta-agonist induced airway relaxation is associated with increases in the phosphorylation of HSP20 and that transducible phosphopeptide mimetics of HSP20 protein as well as recombinant HSP20 protein promote actin depolymerization and relaxation. This proposal will examine how manipulating the expression and phosphorylation of HSP20 affect human airway smooth muscle tone and characterize the molecular events of HSP20- and the phospho HSP20 peptide -mediated actin filament regulation and relaxation. The hypothesis of this investigation is that cyclic nucleotide induced relaxation of human airway smooth muscle is associated with phosphorylation changes of HSP20 and that phospho-peptide mimetics of the small heat shock proteins will circumvent the problems associated with hypo-responsiveness of the beta-agonists in the management of airway constriction.
The aims of this proposal are to 1): Determine if manipulating HSP20 levels affect relaxation of human airway smooth muscle tone through actin cytoskeletal regulation. (2). Optimize the-p-P20 peptides to enhance the bioactivity of the peptides ex vivo using human ASM. 3): Determine the effects of the phospho-HSP20 peptide in vivo in a murine asthma model. These studies will further our understanding of the mechanisms by which HSP20 induces changes in cellular physiology and relaxation of human airway smooth muscle and develop a peptide therapeutic that can circumvent the problems associated with beta-agonists to enhance airway smooth muscle relaxation thus reducing the morbidity, mortality, and costs associated with managing asthma.
Asthma ranks as the third highest reason for preventable hospitalizations in the U.S. and the prevalence of asthma is steadily increasing. The current drug of choice for asthma treatment produces resistance and adverse effects in some patients warranting additional therapeutics for managing asthma. This proposal will identify a phospho peptide that relaxes airway smooth muscle and can be used as a potential drug for asthma and increases our understanding of the mechanism of airway smooth muscle relaxation.