MRTF-SRF signaling in health and disease

Smooth muscle cells regulate vascular resistance and blood pressure.

They also contribute to vascular disease by trans-differentiating from a contractile state into macrophage-like and chondrocyte-like phenotypes that contribute to atherosclerosis.

In contractile cells, alternative cell fates are silenced by a family of transcriptional co-activators called Myocardin-Related Transcription Factors (MRTFs). The transcriptomic impact of MRTFs has started to be uncovered, but insight at the functional level is poor.

Here we leverage RNA-Seq data to identify novel MRTF target genes, and test their function under normal conditions and in disease.

Our specific aims are:To examine if MRTFs confer sensitivity of the vascular wall to the gaseous messenger nitric oxide (NO).To test if the MRTF target gene NEXN protects from aortic aneurysms using a novel transgenic mouse.To address if MRTF signaling drives the biogenesis membrane organelles called caveolae.To examine if MRTFs regulate RRAS, and to test the role of RRAS for cellular quiescence.The work is organized in four work packages and will be conducted over four years by a group of internationally recognized scientists whose expertise in genetics, biochemistry, physiology, and imaging is perfectly tailored for the work at hand.

The project is important because cardiovascular disease represents a major cause of death and disability worldwide and innovative ways to manipulate key disease drivers are desperately needed.