This project aims to define the physiologic and mechanistic functions of RGS proteins, which regulate signaling by hundreds of G protein coupled receptors in the cardiovascular, immune, nervous and sensory systems. Currently it focuses on RGS2, which the P.I. has discovered is an important regulator of blood pressure. The central hypothesis is that RGS2 regulates blood pressure in part by controlling signaling pathways governing vascular tone. This hypothesis is supported by preliminary data showing that: 1) RGS2 knockout mice are hypertensive;2) arteries from RGS2 knockout mice display augmented contraction and unpaired relaxation;3) vascular smooth muscle cells from RGS2 knockout mice exhibit augmented vasoconstrictor-induced Ca2+ signaling and impaired vasodilatory signaling by cGMP-dependent protein kinase (PKG). This project will determine the molecular mechanisms by which RGS2 in concert with PKG regulates signaling pathways that control vascular contraction and relaxation in vascular smooth muscle cells from resistance arteries. In so doing, this project will reveal new mechanistic principles of blood pressure regulation that may be impaired in human hypertension, which would contribute to development of mechanism-based diagnosis and treatment of this poorly understood disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075632-05
Application #
7533445
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Goldman, Stephen
Project Start
2004-12-01
Project End
2010-05-31
Budget Start
2008-12-01
Budget End
2010-05-31
Support Year
5
Fiscal Year
2009
Total Cost
$490,157
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Scherer, Stephanie L; Cain, Matthew D; Kanai, Stanley M et al. (2017) Regulation of neurite morphogenesis by interaction between R7 regulator of G protein signaling complexes and G protein subunit G?13. J Biol Chem 292:9906-9918
Kanai, Stanley M; Edwards, Alethia J; Rurik, Joel G et al. (2017) Proteolytic degradation of regulator of G protein signaling 2 facilitates temporal regulation of Gq/11 signaling and vascular contraction. J Biol Chem 292:19266-19278
Osei-Owusu, Patrick; Blumer, Kendall J (2015) Regulator of G Protein Signaling 2: A Versatile Regulator of Vascular Function. Prog Mol Biol Transl Sci 133:77-92
Osei-Owusu, Patrick; Owens, Elizabeth A; Jie, Li et al. (2015) Regulation of Renal Hemodynamics and Function by RGS2. PLoS One 10:e0132594
Rensing, Derek T; Uppal, Sakshi; Blumer, Kendall J et al. (2015) Toward the Selective Inhibition of G Proteins: Total Synthesis of a Simplified YM-254890 Analog. Org Lett 17:2270-3
Osei-Owusu, Patrick; Knutsen, Russell H; Kozel, Beth A et al. (2014) Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency. Am J Physiol Heart Circ Physiol 306:H654-66
Jia, Lixia; Chisari, Mariangela; Maktabi, Mohammad H et al. (2014) A mechanism regulating G protein-coupled receptor signaling that requires cycles of protein palmitoylation and depalmitoylation. J Biol Chem 289:6249-57
Cain, Matthew D; Vo, Bradly Q; Kolesnikov, Alexander V et al. (2013) An allosteric regulator of R7-RGS proteins influences light-evoked activity and glutamatergic waves in the inner retina. PLoS One 8:e82276
Osei-Owusu, Patrick; Sabharwal, Rasna; Kaltenbronn, Kevin M et al. (2012) Regulator of G protein signaling 2 deficiency causes endothelial dysfunction and impaired endothelium-derived hyperpolarizing factor-mediated relaxation by dysregulating Gi/o signaling. J Biol Chem 287:12541-9
Chinault, Sharon L; Prior, Julie L; Kaltenbronn, Kevin M et al. (2012) Breast cancer cell targeting by prenylation inhibitors elucidated in living animals with a bioluminescence reporter. Clin Cancer Res 18:4136-44

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