Molecular Determinants of Dynamic Blood Pressure Regulation and Cardiovascular Disease - Project Abstract…………………………………………………………………………………………………………… Hypertension is the leading modifiable risk factor for cardiovascular disease (CVD), affecting nearly half of U.S. adults. Despite available therapies, ~80% of individuals with hypertension remain uncontrolled. Current drugs act on relatively few biological pathways, highlighting the need to uncover new mechanisms and therapeutic targets. Most blood pressure (BP) discovery efforts to date have used single, resting BP measurements. However, BP is dynamic, marked by acute variability under stress and gradual shifts with aging. While these dynamic patterns predict CVD beyond BP snapshots, their molecular underpinnings remain undefined, highlighting a gap in our understanding of BP regulation. High-throughput proteomic platforms now measure thousands of proteins in the blood, capturing both genetic and environmental influences that might shape dynamic BP physiology. However, few studies have integrated proteomics with dynamic BP measurements. We recently identified Natural Killer Cell Cytotoxicity Receptor 3 Ligand 1 (NCR3LG1), a trigger for NK cell activity and cytokine release, as associated with the BP response to acute exercise in the HERITAGE Family Study. Notably, genome wide association studies of BP have identified a locus on chromosome 11 that includes NCR3LG1, but without a clear causative gene. Integrating genetics with our proteomic findings, we found NCR3LG1 as the likely causal gene at the locus, underscoring how protein-BP associations highlighted by dynamic BP studies can potentially uncover novel disease mechanisms. We hypothesize that by coupling proteomics with two distinct physiologic stressors, acute exercise and aging, we will uncover latent pathways of BP regulation. In Aim 1, we will identify proteins associated with the acute exercise BP response across HERITAGE and MoTrPAC, two of the largest exercise training cohorts. In Aim 2, we will leverage repeated measures of BP and proteins over time in the population-based cohorts, MESA and JHS, to illuminate the molecular pathways associated with longitudinal BP trajectories. We will integrate genetics with our exercise and aging BP-protein findings to identify causal associations in Mendelian randomization and colocalization analyses. Finally, in Aim 3, we will test whether proteins associated with dynamic BP are linked to CVD. To illuminate CVD pathways, we will also evaluate protein associations with vascular remodeling and endothelial function. Collectively, our proposed research will leverage acute and chronic physiologic stressors of BP, moving beyond static BP snapshots, to find new pathways and potential therapeutic targets for BP and CVD.
