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

Ulcerative colitis (UC) is a complex disorder impacting millions of people worldwide resulting in significant costschronic debilitating symptoms and complications such as colon cancer. Even with biologic therapies targetingimmune 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 havebeen 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 biomarkersfocused on transcriptomics alone are limited. Chromatin the genome folded into 3-D regulates how genesinteract with transcription factors and polymerases to synthesize RNA. Since cytokine signaling converges ontranscription-factor cascades understanding chromatin structure in UC may serve as a rational framework forbiomarker development. The goal of this proposal is to establish a cohesive framework that links transcriptomicstates with chromatin structure for biomarker development in UC. Preliminary work shows that chromatin packingdomains 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 athigh-throughout (>100k independent configurations). We hypothesize that its possible model and predictmacrophage transcriptomic behavior in UC by combining SR-EV with in situ transcriptomic and chromatinmeasurements. We test this hypothesis through three separate but inter-related aims. Aim 1 focuses onexpanding the capabilities of SR-EV to predict domains associated with M1 and M2 macrophage transcriptomicpatterns. Aim 2 studies the mechanisms governing packing domain formation in macrophages and the ability tomanipulate expression by regulating domains. Aim 3 tests how packing domains are transformed UC patientsbefore and after treatment. Collectively this approach expands (1) the structure-function of chromatin inmacrophage signaling (2) develops new technologies for patient care and (3) advances chromatin modeling toaddress heterogeneity in cellular states that can be applied to other diseases in the future. This application is fora K23 Career Development Award for Luay Almassalha M.D. Ph.D. a fellow in Gastroenterology andHepatology at Northwestern Memorial Hospital. Dr. Almassalha will commit the majority of his post-medicaltraining to research studying chromatin packing domains and inflammatory signaling. The division ofgastroenterology and hepatology has an unwavering commitment to his career development. This trainingprogram is tailored to enhance his background in chromatin modeling and imaging and by pairing it with trainingin immunology spatial transcriptomics and clinical investigation. The assembled team of Drs. Parambir Dulai(spatial transcriptomics clinical trials UC) Vadim Backman (chromatin organization nanoscopic imaging) andIgal Szleifer (transcription chromatin modeling) provides a mentorship team unique to Northwestern University.