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Shear Stress : a Master Regulator of the Endothelial Chromatin

Institution: Stanford University
Investigator(s): Jan-Renier Moonen, M.D., Ph.D.
Award Cycle: 2018 (Cycle 27) Grant #: 27FT-0039 Award: $223,884
Subject Area: Cardiovascular and Cerebrovascular Disease
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract

Smoking harms the vascular system because toxic chemicals in cigarette smoke damage endothelial cells, a single layer of cells that forms the inner lining of blood vessels. These cells play very important roles in maintaining healthy vascular function, for instance by preventing blood clotting and regulating blood pressure. When damaged, these cells lose their protective functions, which leads to disease. Endothelial cells are in direct contact with the bloodstream and sense the friction generated by blood flow. Normal blood flow observed in straight parts of the vasculature preserves healthy function by inducing protective genes, while disturbed flow seen at vessel branches induces genes that favor disease. We do not fully understand how exposure to different types of blood flow can protect some cells from the damaging effects of cigarette smoke while making others more vulnerable.

We think that the answer lies in the way our DNA is organized. Every cell in our body has the genetic codes for all our genes, but because different cell types have different functions, not all genes have to be turned on in a specific cell. Genes that are not required are turned off and tightly packed in our DNA. For genes to be active, the DNA has to be unwound to allow certain proteins to bind the DNA and activate the gene. We will study how blood flow affects opening and closing of DNA and how this results in protective or disease-associated gene activation. By understanding the mechanisms and factors that open DNA of protective genes and close DNA of genes that make cells more vulnerable to the damaging effects of cigarette smoke, we can develop better therapies to prevent and treat vascular disease, a major cause of death and disability related to smoking.