Integrating Large-Scale Proteomics and Genomics for the Biological Characterization of Ischemic Stroke in REGARDS

Ischemic stroke is a leading cause of disability and death in the United States. Despite improved preventive therapies, the incidence of ischemic stroke is still unacceptably high. Progress in preventing ischemic stroke events will require a better understanding of their novel risk factors, biological pathways, and causal mediators. Protein levels can serve as potent, specific, and modifiable biomarkers for ischemic stroke risk, guide preventive therapy and elucidate causal mediators and pathways. Large-scale proteomic technology has become available to scan 6,432 distinct plasma proteins (7,596 aptamers) simultaneously using modified aptamers as binding reagents. We will conduct the proteomic investigation in a case-cohort population of 2,000 participants without history of prior strokes from the REGARDS cohort. The overarching goal of this proposal is to improve incident ischemic stroke risk prediction and thus identify high-risk individuals. We will also combine proteomics with genomics to identify proteins that are causal mediators of ischemic stroke and potential new therapeutic targets for stroke prevention. Using artificial intelligence (AI)-based algorithms, we will evaluate the 3-dimensional structure of proteins looking for binding pockets for small molecule ligands (drugs) of potential causal proteins. These findings will be followed by virtual docking experiments that screen libraries of small molecules for their binding to proteins of interest. We will validate key findings from REGARDS in the Multiethnic Study of Atherosclerosis (MESA study). If we are successful, we will: 1) Create protein-based risk scores for incident ischemic stroke with better discrimination and calibration than current models. 2) Identify protein biomarkers, biological pathways, and nominate new therapeutic targets for ischemic stroke. 3) Identify druggable proteins that contain binding sites for small ligands. Docking data can then be used for in vitro screening of small molecule libraries and potential drug therapies. 4) Generalize and reinforce key discoveries in REGARDS by their validation in the MESA study. Project Number: 1R01NS141408-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Rajat Deo (+2 co-PIs) | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $703,249 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 EPH-M (92)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11388917