The long-term goal of this project is to identify functions of RGS proteins and the mechanisms that regulate them. The focus of the present application is RGS2, which has been linked genetically in mice and humans to hypertension. The central hypothesis is that RGS2 regulates blood pressure by carrying out discrete functions in vascular smooth muscle, vascular endothelium, and kidney. This project focuses on the ability of RGS2 to regulate vascular contraction and relaxation by functioning in vascular smooth muscle, endothelium and to regulate fluid transport in renal nephron. It uses cell type- specific RGS2 knockout mice in conjunction with biochemical, cell biological, physiological and imaging methods to address the following Specific Aims: 1) determine how RGS2 degradation is regulated in vascular smooth muscle;2) determine the relative contributions of RGS2 in vascular smooth muscle, endothelium and nephron in blood pressure control;3) determine how RGS2 promotes endothelium-dependent vascular relaxation;and 4) determine whether RGS2 regulates the ability of vasoconstrictors to regulate RhoA signaling ex vivo and in vivo. Accordingly, this project advances understanding of blood pressure control mechanisms and their dysregulation in hypertension, which may contribute to the identification of new hypertension therapies.

Public Health Relevance

Hypertension affects 50 million Americans, making this condition a leading mortality risk factor due to its association with greatly increased risk of cardiovascular disease, renal failure, diabetes and stroke. Hypertension causes enormous clinical and societal burden because ~70% of the patient population is poorly treated by currently available therapeutics. Improved treatment is likely to occur when therapeutics can be tailored to a patient's genetics. This project advances this goal by determining how a newly identified hypertension-linked gene---RGS2-regulates blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075632-09
Application #
8491783
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mcdonald, Cheryl
Project Start
2003-12-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$530,263
Indirect Cost
$181,406
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
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
Jia, Lixia; Linder, Maurine E; Blumer, Kendall J (2011) Gi/o signaling and the palmitoyltransferase DHHC2 regulate palmitate cycling and shuttling of RGS7 family-binding protein. J Biol Chem 286:13695-703
Jayaraman, Muralidharan; Zhou, Hao; Jia, Lixia et al. (2009) R9AP and R7BP: traffic cops for the RGS7 family in phototransduction and neuronal GPCR signaling. Trends Pharmacol Sci 30:17-24
Grabowska, D; Jayaraman, M; Kaltenbronn, K M et al. (2008) Postnatal induction and localization of R7BP, a membrane-anchoring protein for regulator of G protein signaling 7 family-Gbeta5 complexes in brain. Neuroscience 151:969-82
Osei-Owusu, Patrick; Sun, Xiaoguang; Drenan, Ryan M et al. (2007) Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase. J Biol Chem 282:31656-65
Drenan, Ryan M; Doupnik, Craig A; Jayaraman, Muralidharan et al. (2006) R7BP augments the function of RGS7*Gbeta5 complexes by a plasma membrane-targeting mechanism. J Biol Chem 281:28222-31
Drenan, Ryan M; Doupnik, Craig A; Boyle, Maureen P et al. (2005) Palmitoylation regulates plasma membrane-nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family. J Cell Biol 169:623-33
Overton, Mark C; Chinault, Sharon L; Blumer, Kendall J (2005) Oligomerization of G-protein-coupled receptors: lessons from the yeast Saccharomyces cerevisiae. Eukaryot Cell 4:1963-70

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