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 #
5R01HL075632-08
Application #
8282725
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mcdonald, Cheryl
Project Start
2003-12-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$553,575
Indirect Cost
$189,381
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; 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
Zhou, Hao; Chisari, Mariangela; Raehal, Kirsten M et al. (2012) GIRK channel modulation by assembly with allosterically regulated RGS proteins. Proc Natl Acad Sci U S A 109:19977-82
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

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