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.
|Karimi, Ashkan; Milewicz, Dianna M (2016) Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure. Can J Cardiol 32:26-34|
|Wallace, S; Guo, D-C; Regalado, E et al. (2016) Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension. Clin Genet 90:351-60|
|Guo, Dong-chuan; Regalado, Ellen S; Gong, Limin et al. (2016) LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circ Res 118:928-34|
|Jondeau, Guillaume; Ropers, Jacques; Regalado, Ellen et al. (2016) International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet 9:548-558|
|Milewicz, Dianna; Hostetler, Ellen; Wallace, Stephanie et al. (2016) Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene. J Cardiovasc Surg (Torino) 57:172-7|
|Abrams, Joshua; Einhorn, Zev; Seiler, Christoph et al. (2016) Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility and vascular function in zebrafish. Dis Model Mech 9:529-40|
|Kuang, Shao-Qing; Medina-Martinez, Olga; Guo, Dong-Chuan et al. (2016) FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J Clin Invest 126:948-61|
|Chang, Audrey N; Kamm, Kristine E; Stull, James T (2016) Role of myosin light chain phosphatase in cardiac physiology and pathophysiology. J Mol Cell Cardiol 101:35-43|
|Ropars, Virginie; Yang, Zhaohui; Isabet, Tatiana et al. (2016) The myosin X motor is optimized for movement on actin bundles. Nat Commun 7:12456|
|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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