This multidisciplinary Program Project Grant (PPG) is focused on elucidation of fundamental mechanisms that control differentiation and contractile function of vascular smooth muscle cells (SMC) during normal development and maturation, as well as how these control processes are altered in response to vascular injury or diseases such as atherosclerosis, post-angioplasty re-stenosis, and hypertension that are characterized by SMC dysfunction. The Projects are mutually interdependent, highly synergistic, and converge on investigation of a common theme of understanding SMC differentiation, growth, and contractile function. The PPG includes a unique team of internationally recognized investigators with complementary interests and expertise. Project 1 A. Somlyo) is focused on determining the role of the smooth muscle myosin light chain kinase (MLCK) in egulation of development of SMC (with Projects 2 and 3), regulation of cross bridge cycling, and assembly of myosin filaments. Studies also include identification of the kinase(s) responsible for force generation in MLCK knockout mice generated during the current funding period, and collaborative studies examining the role of cytoskeletal remodeling in control of SMC gene expression (Project 2) and differentiation of coronary SMC (Project 3). Project 2 (G. Owens) is focused on determining cellular and molecular mechanisms that control the growth and differentiation of SMC during vascular development, and how these control processes are altered during phenotypic switching of SMC in association with vascular injury or experimental atherosclerosis. Studies include determining the role of myocardin/myocardin-like factors in mediating changes in SMC marker gene expression in response to contractile agonists or PDGF BB that activate or repress SMC gene expression respectively. Studies involve extensive use of unique transgenic and conditional knockout mice generated during the current funding period. Project 3 is new to this PPG and is headed by Dr. Majesky. The goal of this project is to determine the function of vertebrate hedgehog (hh) proteins in coronary SMC development and repair. The project includes extensive joint studies with Project 2 to determine the role ofmyocardin and other SRF co-activators in hh-induced differentiation of coronary SMC, as well as collaborations with both Projects 1 and 2 investigating the role of MLCK and cytoskeletal alterations in differentiation of coronary SMC. A Microscopy Core (Core A) will promote collaborative interactions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL019242-30
Application #
7002718
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Goldman, Stephen
Project Start
1997-01-01
Project End
2009-12-31
Budget Start
2006-01-18
Budget End
2006-12-31
Support Year
30
Fiscal Year
2006
Total Cost
$1,687,720
Indirect Cost
Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Mahoney Jr, William M; Gunaje, Jagadambika; Daum, Guenter et al. (2013) Regulator of G-protein signaling - 5 (RGS5) is a novel repressor of hedgehog signaling. PLoS One 8:e61421
Wu, San-Pin; Dong, Xiu-Rong; Regan, Jenna N et al. (2013) Tbx18 regulates development of the epicardium and coronary vessels. Dev Biol 383:307-20
Dong, Xiu Rong; Majesky, Mark W (2012) Restoring elastin with microRNA-29. Arterioscler Thromb Vasc Biol 32:548-51
Hoglund, Virginia J; Majesky, Mark W (2012) Patterning the artery wall by lateral induction of Notch signaling. Circulation 125:212-5
Salmon, Morgan; Gomez, Delphine; Greene, Elizabeth et al. (2012) Cooperative binding of KLF4, pELK-1, and HDAC2 to a G/C repressor element in the SM22? promoter mediates transcriptional silencing during SMC phenotypic switching in vivo. Circ Res 111:685-96
Alexander, Matthew R; Moehle, Christopher W; Johnson, Jason L et al. (2012) Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. J Clin Invest 122:70-9
Alexander, Matthew R; Murgai, Meera; Moehle, Christopher W et al. (2012) Interleukin-1? modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-?B-dependent mechanisms. Physiol Genomics 44:417-29
Majesky, Mark W; Dong, Xiu Rong; Hoglund, Virginia J (2011) Parsing aortic aneurysms: more surprises. Circ Res 108:528-30
Hoofnagle, Mark H; Neppl, Ronald L; Berzin, Erica L et al. (2011) Myocardin is differentially required for the development of smooth muscle cells and cardiomyocytes. Am J Physiol Heart Circ Physiol 300:H1707-21
Majesky, Mark W; Dong, Xiu Rong; Regan, Jenna N et al. (2011) Vascular smooth muscle progenitor cells: building and repairing blood vessels. Circ Res 108:365-77

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