In Vivo Discovery of Modifiers Restoring Biomechanical Homeostasis in Thoracic Aortopathy

PROJECT SUMMARY – PROJECT 5 Thoracic aortopathy - aortic aneurysms, dissections, and ruptures - is responsible for a significant increase in morbidity and mortality. Over 20 genes have been identified as predisposing patients to developing thoracic aortopathy. Many of these genes are related to abnormal mechanosensing and mechanoregulation of the extracellular matrix by the vascular smooth muscle cells (SMC), which results in decreased energy storage, increased stiffness, and decreased intra-lamellar strength. Importantly, these striking gene associations have not advanced our understanding of the mechanisms underlying this disease and have not enhanced clinical care. Based on advances by our team and others, the overall hypothesis driving this PPG is: aberrant vascular smooth muscle cell-extracellular matrix interactions leading to a loss of biomechanical homeostasis are primary drivers of thoracic aortopathy. Our overall goals are to elucidate the underlying molecular, cellular, and biomechanical mechanisms that drive disease progression and to thereby identify new therapeutic targets. Toward this end, this Project will focus on contributions of cell-matrix interactions that define aortic stiffness and its relation to thoracic aortopathy. First, we will identify primary changes in stiffness-dependent cellular phenotypes in zebrafish models of thoracic aortic aneurysm. We will define common changes in zebrafish carrying key variants (loss of function) of clinical importance: acta2 (Project 1), tgfβr2 (Project 2), and fbn1 (Project 3), each considered further in terms of altered hemodynamic loading (Project 4). Second, we will dissect microRNA-mediated regulation of matrix stiffness genes and examine how cell-mediated loss of biomechanical homeostasis results in disease. Third, we will map the “resiliency” pathway regulating vertebrate SMCs and matrix stiffness in primary variant aortopathy models and manipulate relevant genes to modulate disease phenotypes. This approach will seek not only to block pathological pathways, but also to identify and protect/promote homeostatic reparative pathways to better preserve the structural integrity of the aortic wall.