Christian Park
BME PhD Proposal Presentation
Date: 2024-06-25
Time: 1:00 pm-3:00 pm
Location / Meeting Link: HSRB II N100 / https://zoom.us/j/92099581002?pwd=RzhpN2huUGoyakREOUhVNmNuVXJLdz09 Meeting ID: 920 9958 1002 Passcode: 565900
Committee Members:
Hanjoong Jo, PhD (Advisor); W. Robert Taylor, MD, PhD; Saurabh Sinha, PhD; James Dahlman, PhD; Gregory C. Gibson, PhD
Title: Disturbed Flow Induces Reprogramming of Endothelial Cells to Immune-like and Foam Cells under Hypercholesterolemia during Atherogenesis: From Identification to Therapy
Abstract:
Atherosclerosis, a chronic inflammatory disease characterized by buildup of plaque in the arterial wall and lumen narrowing, is the major underlying cause of heart attack, stroke, and peripheral arterial disease. Despite the widespread use of therapeutics that effectively lower blood cholesterol level, one of the most critical proatherogenic risk factors, atherosclerosis remains to be a leading cause of death worldwide, highlighting the dire need to develop additional therapeutics that target its residual non-lipid aspects. Interestingly, even though hypercholesterolemia, diabetes, and hypertension are systemic risk factors, atherosclerosis preferentially occurs in focal arterial regions exposed to disturbed blood flow (d-flow), while those exposed to stable flow (s-flow) are protected, even under hypercholesterolemia. However, the mechanisms underlying the effects of flow on atherosclerosis on endothelial gene expression and function remain unclear. To address the mechanisms, our lab developed the mouse partial carotid ligation (PCL) model, where ligation of 3 out of 4 downstream branches of the left common carotid artery (LCA) induces d-flow while the contralateral right common carotid artery (RCA) acts as a control exposed to s-flow. Using the PCL model, our lab directly demonstrated that d-flow rapidly and robustly induces atherosclerotic plaque development within 2-3 weeks only under hypercholesterolemia, but not with d-flow or hypercholesterolemia alone. To further explore the mechanisms, our lab previously carried out a single cell RNA-sequencing (scRNA-seq) and single cell assay for transposase-accessible chromatic sequencing (scATAC-seq) study using the PCL model. This study revealed that d-flow alone initiates partial flow-induced reprogramming of endothelial cells (FIRE), including endothelial inflammation, endothelial-to-mesenchymal transition (EndMT), and the novel endothelial-to-immune-like transition partially (partial EndIT). Since d-flow alone cannot induce atherosclerotic plaques without an additional systemic risk factor like hypercholesterolemia, we hypothesize that d-flow under hypercholesterolemia would induce atherosclerotic plaques by inducing robust FIRE, including inflammation, EndMT, and full EndIT. In Aim 1, we will define endothelial reprogramming that occurs in response to d-flow under hypercholesterolemia using scRNA-seq technology. In Aim 2, we will validate FIRE in the mouse arteries during atherogenesis by lineage-tracing and immunostaining methods. In Aim 3, we will define the roles of d-flow-sensitive genes of FIRE in atherogenesis using Perturb-seq screening in vitro and CRISPR-mediated knockdown in vivo. Completion of this study would provide new insights into the mechanism of how d-flow regulates endothelial reprogramming and atherosclerosis for the identification of novel anti-atherogenic therapeutic avenues.
