Project 1 Abstract Accumulating evidence points to an important association between asthma and deficiency of airway S- nitrosoglutathione (GSNO), an association mediated by the enzyme GSNO reductase (GSNOR). Single nucleotide polymorphisms (SNPs) in GSNOR have been linked with asthmatic symptoms and with response to ? adrenergic receptor agonists, while increases in GSNOR activity in human airways have been identified with heightened asthmatic responsiveness. Studies with GSNOR knockout mice support a central role of this enzyme in asthma models. However, GSNOR expression in humans is quite variable and the GSNOR SNP relationships are dependent on the population cohort. Thus, not all patients with asthma have increased GSNOR activity. Here we apply diagnostic tests to identify subsets of asthma patients whose disease can be characterized by GSNO depletion. We will also test the hypothesis that bronchodilatory responsiveness to GSNO and combinations of GSNO and ? adrenergic receptor agonist will be defined by airway GSNOR expression and activity. Because new GSNO-mimetic and GSNO inhibitory agents are in development and early clinical testing, we plan in Cycle II of this program to develop an approach of personalizing these new therapies for those asthma patients with increased GSNOR activity. Ultimately, in collaboration with Projects 2 and 3, we expect that this personalized approach to diagnosing and correcting increased GSNOR activity can be extended to the treatment of CF patients.
Project 1 Narrative Asthmatic patients with increased breakdown of the endogenous bronchodilator S-nitrosoglutathione appear to have characteristic phenotypic features. We plan to develop therapies to correct this phenotype through a combination of mechanistic assessments and clinical testing. We are proposing a novel therapy (S- nitrosylation) that is predicted to provide benefit as a sole-use agent as well as additive benefit when used in combination with other drugs. In addition, the work will synergize with Projects 2 and 3 for which nitrosylation could also be beneficial through modifying airway pH and impacting CFTR, respectively. Finally, we are proposing to develop a new cost-effective easy-to-implement screening approach that can be applied by asthma specialists to manage new severe asthma sub-phenotypes.
| Zhou, Hua-Lin; Stomberski, Colin T; Stamler, Jonathan S (2018) Cross Talk Between S-Nitrosylation and Phosphorylation Involving Kinases and Nitrosylases. Circ Res 122:1485-1487 |
| Powell, Cameron J; Ramaswamy, Raghavendran; Kelsen, Anne et al. (2018) Structural and mechanistic insights into the function of the unconventional class XIV myosin MyoA from Toxoplasma gondii. Proc Natl Acad Sci U S A 115:E10548-E10555 |
| Stsiapura, Vitali I; Bederman, Ilya; Stepuro, Ivan I et al. (2018) S-Nitrosoglutathione formation at gastric pH is augmented by ascorbic acid and by the antioxidant vitamin complex, Resiston. Pharm Biol 56:86-93 |
| Rizza, Salvatore; Cardaci, Simone; Montagna, Costanza et al. (2018) S-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy. Proc Natl Acad Sci U S A 115:E3388-E3397 |
