Hypertension remains the most important risk factor for a wide variety of cardiovascular diseases accounting for approximately 54 percent of all strokes and 47 percent of all ischemic heart disease events globally. Despite the fact that we know there is a significant genetic component that determines the level of blood pressure (estimates of heritability for hypertension range from 30-70%) we are far from understanding the myriad of genetic factors that account for blood pressure (BP) variation in humans. One of the most significant challenges for understanding the vast majority of identified BP-associated genetic variations is dissecting the mechanisms of those variants located in regions of DNA that do not encode proteins. In some cases, these variations affect genes that are hundreds of thousands of base pairs away. We believe that some of these genetic variants may affect how the chromosomes are folded in the cell and affect how blood-pressure related genes interact in those folds to control blood pressure. In this project we will focus on testing the specific hypothesis that chromatin conformation and interaction of BP-related genes with their proper regulatory sequences is important in BP regulation. We will use animal models where we genetically disrupt the chromosomes around genes which are known to play a role in blood pressure regulation. We will also use advanced genomic profiling techniques to identify the locations where these interactions occur for tissues such as blood vessels and segments of the nephron of the kidney that are related to BP regulation and use this data to build an `epigenomic' map of chromatin structure, DNA binding proteins, and other features between rats and humans that will allow us to identify and study similar mechanisms for other genes. This project is highly collaborative with the other projects and cores in this Program Project Grant through the sharing of reagents (cells and tissues), transfer of data, and the intellectual environment of the investigators and their laboratories. .
