Uncovering Cross-Disease Platelet Transcriptomic Signatures to Advance Precision Medicine - PROJECT SUMMARY Cardiovascular, immune-mediated, cancer, and hematologic diseases, including myeloproliferative neoplasms (MPNs), represent major public health burdens. Despite extensive research on these conditions, gaps remain in our understanding of the role of platelets across these diverse disease processes. Platelets contribute not only to hemostasis but also play integral roles in inflammation, immune response, and disease progression. Their molecular functions in these processes, however, are incompletely understood, which limits the development of targeted, cross-disease diagnostic and therapeutic strategies. Identifying common molecular pathways in platelets across these disease categories is crucial for informing biomarker discovery and universal therapeutic targets, ultimately advancing precision medicine for NHLBI-relevant diseases. This proposal aims to bridge critical knowledge gaps by examining platelet transcriptomes across cardiovascular, immune-mediated, cancer, and hematologic diseases, identifying shared and unique molecular pathways. Utilizing curated platelet RNA-sequencing datasets from over 2,000 ancestrally diverse individuals with varied phenotypes, we will leverage advanced machine learning and bioinformatics tools to elucidate these cross-disease signatures. Aim 1 will employ methods such as Identifiable Deep Generative Models (DGM), Non-negative Matrix Factorization (NMF), and Principal Component Analysis (PCA) to compare platelet transcriptomic profiles across cardiovascular, immune-mediated, cancer, and hematologic conditions. This analysis aims to reveal common and unique pathways, which may serve as shared biomarkers or therapeutic targets. Aim 2 will focus on constructing a comprehensive, functionally annotated multi-disease platelet transcriptomic atlas. This resource will analyze gene expression patterns, isoforms, alternative splicing, and allele-specific expression variations, providing valuable insights into the conserved and disease-specific functions of platelets. Completion of these aims will yield a novel, cross-disease platelet transcriptomic atlas, offering an invaluable resource for biomarker discovery and therapeutic interventions in NHLBI-relevant diseases. This research not only addresses critical gaps in our understanding of platelet biology but also aims to enhance clinical applications in precision medicine, advancing patient care for diverse populations affected by these high-impact diseases.
