Project 4 will address the central PPG hypothesis that ACTA2 and MYH11 mutations decrease force generation by SMCs and lead to thoracic aneurysms in the aorta and occlusive vascular diseases in smaller arteries through activation of different and distinct pathways. Genetically modified mouse models of ACTA2 and MYH11 mutations identified in familial thoracic aortic disease will be characterized for thoracic aortic aneurysm formation and neointimal formation with vascular injury, and the proliferation of explanted aortic smooth muscle cells (SMCs) determined. Project 4 will characterize the tissue and cellular alterations related to the aneurysm progression and neointimal formation in vivo, along with assessing pathway leading to SMC proliferation in vitro. Finally, we will continue to identify genotypes and correlating phenotypes of patients with ACTA2 and MYH11 genetic variants to delineate the full range of genotypes, the associated phenotypes and begin to delineate the associated vascular disease risk.
This study will identify the cell signaling, growth factors and cytokines, and proteases that lead to thoracic aortic aneurysms and dissections in a mouse model of the disease. Additionally, these studies will identify the pathways leading to increased neointimal formation associated with mutations in ACTA2.
|Milewicz, Dianna M; Regalado, Ellen S; Shendure, Jay et al. (2014) Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc Med 24:53-60|
|Kwartler, Callie S; Chen, Jiyuan; Thakur, Dhananjay et al. (2014) Overexpression of smooth muscle myosin heavy chain leads to activation of the unfolded protein response and autophagic turnover of thick filament-associated proteins in vascular smooth muscle cells. J Biol Chem 289:14075-88|
|Qiao, Yan-Ning; He, Wei-Qi; Chen, Cai-Ping et al. (2014) Myosin phosphatase target subunit 1 (MYPT1) regulates the contraction and relaxation of vascular smooth muscle and maintains blood pressure. J Biol Chem 289:22512-23|
|Regalado, Ellen S; Guo, Dong-chuan; Estrera, Anthony L et al. (2014) Acute aortic dissections with pregnancy in women with ACTA2 mutations. Am J Med Genet A 164A:106-12|
|Tsai, Ming-Ho; Chang, Audrey N; Huang, Jian et al. (2014) Constitutive phosphorylation of myosin phosphatase targeting subunit-1 in smooth muscle. J Physiol 592:3031-51|
|Nelson, Michael D; Rader, Florian; Tang, Xiu et al. (2014) PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology 82:2085-91|
|Guo, Dong-chuan; Regalado, Ellen; Casteel, Darren E et al. (2013) Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet 93:398-404|
|Gao, Ning; Huang, Jian; He, Weiqi et al. (2013) Signaling through myosin light chain kinase in smooth muscles. J Biol Chem 288:7596-605|
|Kuang, Shao-Qing; Geng, Liang; Prakash, Siddharth K et al. (2013) Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade. Arterioscler Thromb Vasc Biol 33:2172-9|
|Barua, Bipasha; Fagnant, Patricia M; Winkelmann, Donald A et al. (2013) A periodic pattern of evolutionarily conserved basic and acidic residues constitutes the binding interface of actin-tropomyosin. J Biol Chem 288:9602-9|
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