The long-term goal of this project is to understand the molecular mechanisms that regulate smooth muscle cell (SMC) phenotypic changes during smooth muscle myogenesis and in the pathogenesis of human vascular diseases. Recent extensive biochemical and genetic studies have provided substantial evidence showing that the balance of histone acetylation and deacetylation is crucial to the control of cell proliferation in cancer and cardiac hypertrophy. However, little is known about how manipulating histone acetylation controls SMC gene transcription and proliferation in human vascular diseases. The goal of this application is to determine the molecular mechanisms whereby histone modifiers, especially HDAC8, regulate SMC gene transcription both in vitro and in vivo. This study integrates innovative transgenic/knockout mice, BAG recombineering and bioinformatics tools into classic biochemical, molecular and developmental biology approaches. The results of this study will not only fill a gap in our understanding of HDACs in transcriptional regulation, but also further our knowledge of epigenetic mechanisms in regulating SMC myogenesis^ Extensive studies demonstrate that the dynamic changes of histone acetylation and deacetylation play important roles in gene transcription and cell proliferation. HDACS is a member of the class I HDAC (histone deacetylase) family, and possesses histone deacetylase activities. Our preliminary results show that HDACS, unlike other HDACs, acts as a transcriptional activator for SMC gene transcription. We hypothesize that HDACS is a pro-SMC differentiation factor that modulates SRF/Myocardin and SmadS-mediated SMC transcriptional regulatory complexes.
The specific aims are: (1) to determine whether HDACS affects histone modification at the SM22 locus in vitro, and whether the deacetylase activity of HDACS is required to enhance the pro-myogenic activities of SMC regulators;(2) to determine how HDACS interacts with the SMC transcriptional regulatory network and TGFpl signal pathway;(3) to determine whether histone deacetylase inhibitors affect atherogenesis and how HDACS modulates SMC differentiation in SMC myogenesis and in injury-induced restenosis in vivo. Given the important roles of histone modification in SMC growth and differentiation, the results of this study will contribute significantly towards developing novel therapeutical strategies targeted at the epigenetic mechanisms affecting the abnormal SMC-associated human vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087014-05
Application #
8085715
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Olive, Michelle
Project Start
2007-07-06
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$376,250
Indirect Cost
Name
Wayne State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Dai, Xiaohua; Shen, Jianbin; Annam, Neeraja Priyanka et al. (2015) SMAD3 deficiency promotes vessel wall remodeling, collagen fiber reorganization and leukocyte infiltration in an inflammatory abdominal aortic aneurysm mouse model. Sci Rep 5:10180
Xu, Ying-Ping; Shi, Yuling; Cui, Zhi-Zhong et al. (2012) TGF?/Smad3 signal pathway is not required for epidermal Langerhans cell development. J Invest Dermatol 132:2106-9
Xu, Zhonghui; Ji, Guangdong; Shen, Jianbin et al. (2012) SOX9 and myocardin counteract each other in regulating vascular smooth muscle cell differentiation. Biochem Biophys Res Commun 422:285-90
Shen, Jianbin; Yang, Maozhou; Jiang, Hong et al. (2011) Arterial injury promotes medial chondrogenesis in Sm22 knockout mice. Cardiovasc Res 90:28-37
Zheng, Jian-Pu; Ju, Donghong; Jiang, Hong et al. (2010) Resveratrol induces p53 and suppresses myocardin-mediated vascular smooth muscle cell differentiation. Toxicol Lett 199:115-22
Shen, Jianbin; Yang, Maozhou; Ju, Donghong et al. (2010) Disruption of SM22 promotes inflammation after artery injury via nuclear factor kappaB activation. Circ Res 106:1351-62
Yang, Maozhou; Jiang, Hong; Li, Li (2010) Sm22? transcription occurs at the early onset of the cardiovascular system and the intron 1 is dispensable for its transcription in smooth muscle cells during mouse development. Int J Physiol Pathophysiol Pharmacol 2:12-9
Zheng, Jian-Pu; Ju, Donghong; Shen, Jianbin et al. (2010) Disruption of actin cytoskeleton mediates loss of tensile stress induced early phenotypic modulation of vascular smooth muscle cells in organ culture. Exp Mol Pathol 88:52-7