OVERALL PROGRAM SUMMARYOne of the most significant challenges for understanding genetic control of blood pressure (BP) is that the vastmajority of BP-associated single nucleotide polymorphisms (SNPs) in humans are located in noncodingregions of DNA. Many of these noncoding SNPs are located in haplotype regions thousands of base pairsaway from any protein-coding gene and their effects on BP cannot be explained by any currently known codingor other functional sequence variant making it nearly impossible to link these noncoding SNPs to genes orphysiological pathways that regulate BP based on genomic sequence. Understanding the effect of intergenicnoncoding SNPs on gene expression and the underlying mechanisms is a major challenge not just for BP andhypertension research but for research on nearly all complex traits and common diseases. The goal of this PPG proposal is to begin to address this major challenge and test the overallhypothesis that noncoding SNPs associated with human BP but located far from any protein-codinggene regulate gene expression in specific BP relevant cell types through epigenetic mechanisms andthese mechanisms can influence BP. We have developed three projects that each address one aspect ofthis overall hypothesis. Project 1 will use precision genome editing to identify the effect of specific BP-associated noncoding SNPs on gene expression in BP-relevant human cell types. Project 2 will test thehypothesis that BP-associated noncoding SNPs influence the expression of BP-relevant genes throughepigenetic mechanisms including chromatin looping enhancer function and noncoding RNA in human cellsand tissues. Project 3 will take this line of research to animal models in vivo to test directly the novelhypothesis that chromatin conformation plays a role in BP regulation. The three projects will interact with andinform each other extensively and together will achieve the overall goal of the program. All three projects willrely on Core A for administrative support and Core B for sequencing coordination and data analysis. We have published at least 16 papers in the last few years that provide direct support for key aspects ofthe conceptual validity and technical feasibility of this PPG. In addition we have obtained a large amount ofpreliminary data to further support the feasibility of the wide range of sophisticated and new technologies thatwe will use and the validity of proposed novel hypotheses. This PPG represents a fundamentally new directionfor hypertension research. It will establish several novel approaches and technologies generate unique andextensive datasets and provide new biological insights all of which will help to advance genetic and epigeneticresearch in hypertension and other disease areas.