From molecules to medicine : expanding the therapeutic streetlight for inflammatory bowel diseases
- Inflammatory bowel diseases (IBD) comprise a set of largely heterogeneous chronic intestinal disorders and includes ulcerative colitis (UC) and Crohn's disease (CD). Compounding prevalence of IBD, exacerbated by relatively early disease onset, low mortality, and lack of curative therapies, has led to an increasing economic burden on the healthcare system. There may be subsets of patients with IBD whose molecular underpinnings are not yet addressed in the current paradigm of IBD translational research and drug development. This includes epigenetics, which is understudied and could provide mechanistic links between environmental influences and IBD pathology. It is imperative to continue the investigation of novel modalities that may explain more nuanced manifestations of IBD and develop new therapies with the ultimate goal of improving care for patients with IBD. Here, we aimed to address the critical need for novel drug treatments for patients with IBD in two ways. First, we implemented computational drug repositioning via signature matching using publicly available gene expression datasets to identify FDA-approved drugs that can be repurposed to treat patients with UC. We identified atorvastatin as a lead candidate for reversing inflammatory genes from the disease signature, and we validated our findings using a retrospective cohort study design modeled after a target trial and showed that atorvastatin had a protective effect on colectomy risk in patients with UC. Our findings provide a systematic framework for integrating at a large scale to repurpose existing FDA-approved drugs for a wide range of human diseases beyond UC. Secondly, we report single-cell histone acetylation and methylation shifts in multiple hematopoietic cell types from patients with IBD. Using epigenetic landscape profiling by time-of-flight mass cytometry (EpiTOF), we investigated histone and chromatin modification changes in peripheral blood mononuclear cells (PBMCs) from patients with IBD that may peripherally inform local tissue immune responses under disease conditions. Our findings support a role for histone modifications in IBD pathology that can offer new insights into the epigenomic landscape of IBD and ultimately opens the door to a novel class of therapeutics that may be efficacious for patients with IBD.
|Type of resource
|electronic resource; remote; computer; online resource
|1 online resource.
|Degree committee member
|Degree committee member
|Stanford University, Program in Immunology
|Statement of responsibility
|Submitted to the Program in Immunology.
|Thesis Ph.D. Stanford University 2021.
- © 2021 by Lawrence Bai
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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