Familial thoracic aortic aneurysms and dissection (TAAD) are linked to mutations in smooth muscle myosin heavy chain, actin and myosin light chain kinase (MLCK. We will test the overarching hypothesis that disease-causing mutations reduce smooth muscle contractile function.
Aim 1 : Test the hypothesis that MYH11 mutations that cause TAAD impair contractile output of smooth muscle cells. We will analyze aortic smooth muscle tissues from genetically modified mice for age-dependent adaptive changes in (1) expression of proteins in distinct adhiesion and contractile signaling modules, (2) [Ca2+]i and vasomotor performance in tissue rings in response to agonists, and (3) phosphorylation that activates the contractile myosin (RLC) or focal adhesion (paxillin) signaling modules.
Aim 2 : Test the hypothesis that heterozygous loss of MLCK activity impairs contractile output because of attenuated RLC phosphorylation in smooth muscle cells and leads to development of TAAD in the ascending aorta.
Aim 3 : Test the hypothesis that ACTA2 mutations that cause TAAD impair contractile output of smooth muscles. We will analyze the adhesion and contractile signaling modules as described in Aim 1 to determine if specific actin mutations promote selective dysfunction in one module or both.
Aim 4 : Test the hypothesis that ACTA2 mutations perturb myofibroblast contractions. MRTF-A will be used to induce myofibroblast phenotype expressing high amounts of smooth muscle a-actin in human dermal fibroblasts from patients harboring mutations in ACTA2. These studies will provide insights into the cellular basis of contractile performance defects associated with ACTA2 and MYH11 mutations examined at a molecular level in research Projects 1 and 2, and cellular pathways associated with reorganization of focal adhesions in mutant cells (Project 4). We also will continue collaborative studies on MLCK with Project 4.The synergy of our research interactions will provide an understanding of the molecular mechanisms that influence vascular disease based on the hypothesis that ACTA2, MYH11 and MYLK mutations lead to TAAD and occlusive vascular diseases due to selective dysfunctions of the contractile process.
We plan to establish the quantitative importance specific proteins responsible for the contractile responses of smooth muscle cells in blood vessels in health which may be deranged with mutations associated with TAAD. Characterization of key signaling proteins will provide perspectives on clinical strategies for novel pharmacological targets to manage TAAD, and potentially on cellular adaptations that may contribute to derangement of contractile responses involving smooth muscle in other vascular diseases.
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