Predictive modeling of CD-68 inflammatory and anti-inflammatory chromatin packing domains for personalized biomarker discovery

Northwestern University At Chicago, Evanston IL

Investigators

Abstract

Project Summary/Abstract Ulcerative colitis (UC) is a complex disorder impacting millions of people worldwide resulting in significant costs, chronic debilitating symptoms, and complications such as colon cancer. Even with biologic therapies targeting immune signaling pathways, variability in patient responses is highly prevalent and remission rates remain low (~40%). Therefore, personalized biomarker development is an area of unmet clinical need. Macrophages have been identified as a crucial intermediary of pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes in UC. Due to the significant overlap between M1 and M2 signaling even in histologically identical tissues, biomarkers focused on transcriptomics alone are limited. Chromatin, the genome folded into 3-D, regulates how genes interact with transcription factors and polymerases to synthesize RNA. Since cytokine signaling converges on transcription-factor cascades, understanding chromatin structure in UC may serve as a rational framework for biomarker development. The goal of this proposal is to establish a cohesive framework that links transcriptomic states with chromatin structure for biomarker development in UC. Preliminary work shows that chromatin packing domains are the primary regulator of transcriptional reactions in cells. The stochastic returns-excluded volume (SR-EV) model can produce the structure of chromatin packing domains observed on electron microscopy at high-throughout (>100k independent configurations). We hypothesize that it’s possible model and predict macrophage transcriptomic behavior in UC by combining SR-EV with in situ transcriptomic and chromatin measurements. We test this hypothesis through three separate but inter-related aims. Aim 1 focuses on expanding the capabilities of SR-EV to predict domains associated with M1 and M2 macrophage transcriptomic patterns. Aim 2 studies the mechanisms governing packing domain formation in macrophages and the ability to manipulate expression by regulating domains. Aim 3 tests how packing domains are transformed UC patients before and after treatment. Collectively, this approach expands (1) the structure-function of chromatin in macrophage signaling, (2) develops new technologies for patient care, and (3) advances chromatin modeling to address heterogeneity in cellular states that can be applied to other diseases in the future. This application is for a K23 Career Development Award for Luay Almassalha, M.D., Ph.D., a fellow in Gastroenterology and Hepatology at Northwestern Memorial Hospital. Dr. Almassalha will commit the majority of his post-medical training to research studying chromatin packing domains and inflammatory signaling. The division of gastroenterology and hepatology has an unwavering commitment to his career development. This training program is tailored to enhance his background in chromatin modeling and imaging and by pairing it with training in immunology, spatial transcriptomics, and clinical investigation. The assembled team of Drs. Parambir Dulai (spatial transcriptomics, clinical trials, UC), Vadim Backman (chromatin organization, nanoscopic imaging) and Igal Szleifer (transcription, chromatin modeling) provides a mentorship team unique to Northwestern University.