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Abstract or Project Description

Abstract or Project Description

Accumulating data supports the concept that IBD has a preclinical period that may be amenable to early diagnosis and intervention. Understanding the molecular underpinnings of this preclinical period in disease pathogenesis offers new opportunities in risk prediction and prevention. We have recently reported the first data from a large study using longitudinal pre-diagnostic samples from the US Department of Defense Serum repository, the PREDICTS study, where we assessed the predictive value of a panel of antimicrobial markers and a proteomic panel (>1100 proteins). Additional –omics data including glycan profiles, metabolome and exposome are currently generated on these same samples that span from up to 5 years before diagnosis to first clinical symptoms and confirmed diagnosis. We will integrate these massive multi-omics datasets to develop machine-learning (ML) based models predictive of future progression of CD and UC years before diagnosis, and to discover driver biomarkers and biological processes responsible for disease initiation. This will be achieved by constructing time-varying disease-specific networks capturing the associations across all biomarkers measured at different years before diagnosis available through the PREDICTS initiative. We will make all results publicly available via a user-friendly web-platform to facilitate the easy query, exploration and utilization of these data.

Abstract or Project Description

Inflammatory Bowel Diseases (IBDs) are typified by bouts of inflammation-induced epithelial damage and repair. By take cues from their microenvironment or “niche”, intestinal stem cells (ISCs) direct these fluctuating pathological and reparative states in IBD. Yet, we do not understand which cells comprise the inflamed ISC niche and how they switch on programs of repair. To track evolving ISC niches, we are proposing the development of a new cutting-edge Niche-labeling system. Our ultimate goal is to understand how ISC niches change over the course of disease and leverage this information to reprogram an “inflammatory ISC niche” into a “regenerative ISC niche” and achieve lasting remission in IBD.

Abstract or Project Description

The microbes that flourish within our guts are central to many aspects of human health. Which microbes are present can dictate susceptibility to a number of acute and chronic diseases, including IBD. This proposal will use a mouse model with a defined and stable set of bacteria to probe how mice interact with specific members of their microbiota in health and during disease. First, each microbe will be tested for its ability to elicit an immune response in healthy mice. Once we have established the baseline response in normal healthy mice, we will use chemicals to disrupt the gut lining to elicit an inflammatory response, or we will disrupt genes known to limit intestinal inflammation. We will then investigate how immune recognition of the microbiota changes under these altered conditions. This system will enable us to track responses to the microbiota with unprecedented precision and will provide clues regarding which microbes drive immune activation during dysregulated responses to the microbiota. Such studies will pave the way for future work aimed at manipulating responses to key members of the microbiota responsible for inflammatory diseases of the gut.

Abstract or Project Description

Gut inflammation alters the bacterial communities in the gut (the microbiome), and these disruptions are thought to make inflammation even worse. Understanding and derailing this cycle could provide new avenues for IBD therapy. Although we know that inflammation can change “who’s there” in the gut microbiome, this project will determine whether harder-to-measure changes within the microbiome also impact the cycle of inflammation and microbiome disruption. Specifically, we will study whether episodes of inflammation cause these bacteria to change by altering their genetic instructions or how those instructions are read out. If successful, the study will uncover new measurements that we need to collect in order to understand how an individual’s microbiome responds to flares of inflammation and remission in IBD. In the future, this understanding will help us design microbiome-based therapies equipped to persist in the inflamed gut and break the cycle of microbiome disruption and inflammation that characterizes IBD.

Abstract or Project Description

We have discovered a novel single-gene defect in patients with pediatric IBD, setting the stage for new molecular and cellular discoveries to dissect biology stemming from human disease. Here, we will pursue two aims that will open new doors by leveraging the strength of preclinical models to uncover mechanisms by which the gene we identified in patients orchestrates immune responses and inflammation in the gastrointestinal tract. Specifically, we will assess roles for this gene in regulating production of the inflammatory IL-1 cytokine and begin to dissect interplay between immune cells lacking this gene and bacteria in the intestine. Since our work begins with patients, our findings will be directly translatable between humans and mice and will advance our unbiased gene discovery to mechanistic insights more broadly relevant for mapping immune interactions relevant for the larger IBD community. Together, these aims address innovative new hypotheses and will advance the mission of the Kenneth Rainin Foundation by enabling transformative IBD discoveries rooted in human biology and advanced with powerful modeling approaches.