Shankar Subramaniam
University of California San Diego

“Multi-Omics Systems Biology Approach to
Vascular Biology”

Abstract:

Over the past decade, we have investigated the mechanisms associated with shear stress response in endothelial cells using systems biology approaches [e.g. 1-8]. In the most recent granting period, we have carried out longitudinal analysis of distinctive shear stress response to pulsatile and oscillatory stress corresponding to normal and disturbed flow in blood vessels. Our studies have provided fundamental insights into temporally regulated mechanisms as well as a systems-level view of stress response. Our key findings also included implications of long noncoding RNA molecules – LEENE and LINC341 - which appear to have dramatic consequences on endothelial homeostasis. The regulation by LINC RNAs entails the coupling between KLF4 and genes involved in endothelial function. In addition, we explored the interplay between endothelial cells and macrophages in atherogenesis. These studies reveal a novel mechanisms in which the transcription factor KLF4 regulates the enzyme cholesterol-25-hydroxylase and the nuclear hormone receptor Liver X Receptor. Our key findings indicate that KLF4 transactivates cholesterol-25-hydroxylase and liver X receptor, thereby promoting the synergistic effects between ECs and macrophages to protect against atherosclerosis susceptibility.

Acknowledgements: Supported by NHLBI Grants R01HL106579 and HL108735; Collaborative projects with Drs. Shu Chien and John Shyy Laboratories