The human smooth muscle myosin heavy chain is the target of mutations that can cause familial thoracic aortic aneurysm dissection (TAAD). The underlying irnpact of the mutations is unknown, but it has been speculated that the mutations cause decreased force output in the smooth muscle cells. Intriguingly, mutations in similar regions of the human smooth muscle myosin have been associated with colorectal (CR) cancer, while other mutations are associated with intracranial aneurysms (ICA). In the case of the cancer- associated mutations, features shared with the TAAD-causing mutations that we have examined to date are a loss of regulation and altered kinetics that are consistent with decreased force output. We hypothesize that that a critical feature of the TAAD mutations that leads to disease is the loss of regulation. We hypothesize that the ICA-associated mutations will have a differential impact that will distinguish them from the TAAD- causing mutations. This likely will be altered contractile function without any loss of regulation. This will allow us to develop diagnostic evaluations of protein function that may prove of predictive value as to the consequences of mutations detected in patients prior to disease onset. This proposal makes use of our ability to express large amounts of human smooth muscle myosin in SF9 cells. We will characterize the impact of TAAD and ICA mutations on the kinetics, motility and regulation of human smooth muscle myosin, as well as examine filament forming properties and the impact on force generation at the ensemble and single molecule level for a subset of the mutations.

Public Health Relevance

A number of genes have been linked to thoracic aortic aneurysms leading to type A dissections (TAAD). This project seeks to study the effect of the mutations in myosin in sufficient detail to allow an understanding of the pathological processes that takes place, which in turn could lead to new insights and better treatments for the diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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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
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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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