Our laboratory is using cellular, molecular, bioengineering, and computational biology tools to understand how mechanical forces generated by the flow of blood act on blood vessels to activate signaling pathways critical for cellular specification during developmental processes, and for flow-mediated vasoprotection in the context of human cardiovascular disease.
BIOMECHANICAL CONTROL OF EMBRYONIC DEVELOPMENTAL PROCESSES
When the heart starts beating and blood flow is first established during vertebrate development endothelial cells lining nascent blood vessels are first expose to hemodynamic forces. The effects this critical developmental transition has on the developing vascular system remain poorly characterized. We are currently studying two processes related to this transition namely, arterial specification and the induction of embryonic hematopoiesis via the flow-mediated specification of the hemogenic endothelium.
BIOMECHANICAL CONTROL OF ENDOTHELIAL VASOPROTECTION
In experiments design to probe the transcriptional machinery responsible for the endothelial vasoprotective phenotype present in regions of the human vasculature resistant to atherosclerosis, we revealed that the transcription factor Kruppel-like factor 2 (KLF2) acts as an integrator of the flowmediated endothelial vasoprotective phenotype. Importantly, we demonstrated that Statins, one of the most widely used class of drugs for cardiovascular disease, increase the expression of KLF2, explaining in part, the well-described non-lipid lowering, vasoprotective effects of this class of drugs. These observations have led us to initiate high-throughput screens to identify small molecules and siRNAs capable of regulating KLF2 expression. These experiments should enable us to dissect mechanistically how flow leads to the expression of KLF2, and could aid in the identification of new therapeutics capable of mimicking natural mechanisms of vasoprotection.
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