Maher Saadeh
BME PhD Proposal Presentation
Date: 2024-09-16
Time: 3:00 PM - 5:00 PM
Location / Meeting Link: HSRB II N600 Zoom: https://emory.zoom.us/j/95255175316?from=addon.
Committee Members:
Holly Bauser-Heaton MD, PhD (Advisor); Vahid Serpooshan PhD; Lakshmi Prasad Dasi PhD; Wilbur Lam MD, PhD; Hee Cheol Cho, PhD
Title: 3D Bioprinted Pulmonary Artery Model for Williams Syndrome Vascular Pathology
Abstract:
Long-term treatment strategies for patients with pulmonary artery stenosis (PAS) remains ineffective due to the heterogenous nature of stenosis development. Researchers have demonstrated how PAS phenotype varies depending on the congenital heart defect (CHD) or genetic syndrome the patient possesses. Williams Syndrome (WS) is a deletion of the ELN gene is known to disrupt physiologic function of smooth muscle cells (SMCs) due to insufficient elastin-SMC linking, which causes SMC dedifferentiation to its proliferative state. This indicates a possible mechanical reason for WS stenosis development; however, not all WS patients express PAS and, when present, it is located are at the bifurcation points of the pulmonary vascular tree. This indicates that flow, specifically wall shear stress (WSS), and cyclic strain could be mechanical stimuli that triggers PAS. The major goal of this proposal is to uncover discrepancies in mechanotransduction signaling induced by WSS and cyclic strain utilizing models of normal and WS cells. Current pulmonary artery models, in vivo and in vitro, are being used to uncover this mechanism, but they are unable to recapitulate the cellular and mechanical environment that exists during stenosis pathogenesis. Therefore, to understand PAS disease pathogenesis and the reason why WS patients have PAS, we need a model that can be tuned to various genetic disease conditions. In this proposal, we intend to develop a model to accurately analyze cellular mechanotransduction pathways found in the pulmonary vascular system (Aim 1). Our hypothesis is that a tunable, patient-specific 3D bioprinted model of the pulmonary artery, containing normal or WS EC and SMC co-cultured in distinct layers, will demonstrate alterations in mechanical conditions will activate tropoelastin related mechanotransduction pathways, demonstrating a cell to ECM synthesis disconnect in WS (Aim 2). We intend to do this by finding the upregulation of mechanotransduction signaling in a flow and pulsatile environment using scRNA-seq. We also will repurpose a drug, sirolimus, to see if we can rescue the WS cell elastin signaling (Aim 3). This work will allow us to identify initial vascular cellular responses in acute non-homeostatic conditions and uncover unique signaling pathways found in CHD related PAS. This fundamental knowledge from our vascular mimics can then be applied to facilitate translational advancements in treatment of PAS via surgical and transcatheter methods.