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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL110869-02
Application #
8536679
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$467,865
Indirect Cost
$160,060
Name
University of Texas Health Science Center Houston
Department
Type
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
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Regalado, E S; Guo, D C; Santos-Cortez, R L P et al. (2016) Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections. Clin Genet 89:719-23

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