[K23] Predictive modeling of CD-68 inflammatory and anti-inflammatory chromatin packing domains for personalized biomarker discovery
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2030-04-30
Importo max: 187.038 EUR
Paese: US
Descrizione
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 investigatio
Istituzione: NORTHWESTERN UNIVERSITY AT CHICAGO
PI: Luay Matthew Almassalha
Progetto: 5K23DK144661-02
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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