This application is designed to enable the principal investigator to develop as an independent physician-scientist in the field of pulmonary vascular biology. Under the co-mentorship of two established investigators, Dr. Jonathan Stamler and Dr. Robert Lefkowitz, the P.I. will gain new expertise in the study of alpha-adrenergic receptor function in the pulmonary vasculature and substantially strengthen her level of expertise in NO biochemistry and protein modification by Snitrosylation. Preliminary data show that pulmonary vasoconstriction by a-adrenergic agonists is attenuated by the endothelial- derived relaxing factor, nitric oxide (NO). NO (or molecules derived from it) is known to regulate protein function by chemical modifications of cysteine residues, i.e. Snitrosylation.
The specific aims test the hypothesis that NO regulates pulmonary vascular tone by chemically modifying alpha1Beta-adrenergic receptors in pulmonary vascular smooth muscle.
Aim 1) Determine which components of (alpha1-adrenergic receptor signaling are modified by NO to antagonize vasoconstriction.
Aim 2) Determine whether NO S-nitrosylates the (alpha1-adrenergic receptor or other targets detected in Aim 1, and identify the cysteines involved.
Aim 3) Investigate the role and mechanisms of constitutive and inducible nitric oxide synthase isoforms in the regulation of a1-adrenergic function in vitro and in vivo. Experiments will be performed in HEK293 transfected with alpha1beta-adrenergic receptor (Aims 1 and 2), cultured rat pulmonary vascular cells and PA rings (Aim 3). This proposal will also establish whether the effects of NO are specific for the (alpha1-adrenergic receptor or represent a general mechanism for NO to regulate G-protein coupled receptor signaling. Understanding the factors that regulate pulmonary vascular function will lead to rational development of new therapies for lung diseases that affect the pulmonary blood vessels.
| Auten, Richard L; O'Reilly, Michael A; Oury, Tim D et al. (2006) Transgenic extracellular superoxide dismutase protects postnatal alveolar epithelial proliferation and development during hyperoxia. Am J Physiol Lung Cell Mol Physiol 290:L32-40 |
| Nozik-Grayck, Eva; Whalen, Erin J; Stamler, Jonathan S et al. (2006) S-nitrosoglutathione inhibits alpha1-adrenergic receptor-mediated vasoconstriction and ligand binding in pulmonary artery. Am J Physiol Lung Cell Mol Physiol 290:L136-43 |
