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Abstract or Project Description

Abstract or Project Description

Ulcerative colitis (UC) is a chronic inflammatory disorder that affects the colon. There are multiple types of cells that drive inflammation and injury to the lining of the colon. Vedolizumab (VDZ) is a medication that blocks circulating immune cells from gaining access to the colon, but there are conflicting data about the primary cell types affected by this treatment. To identify the inflammatory cells that contribute to colitis and respond to VDZ, we performed a comprehensive single-cell transcriptomic and proteomic analysis of peripheral blood and colonic biopsies of patients with and without UC. We identified inflammatory cells called mononuclear phagocytes (MNPs) as a primary target of VDZ. We then used four new, complementary methods to look at where these cells are located in fixed tissue sections, and we discovered increased density and proximity of MNP and fibroblast subsets in UC biopsies when compared to HC, with inhibition by VDZ. We now want to confirm and extend these findings by looking in more detail at these cell types in tissue sections before and after therapy. We also want to culture epithelial cells from patients with MNPs and fibroblasts to see how these cells interact when grown in the lab.

Abstract or Project Description

T cells are major drivers of Inflammatory Bowel Disease (IBD) but the full set of factors promoting inflammatory intestinal T cell accumulation in affected individuals is not understood. We have found that deficiency in a signaling molecule (G-protein) in mouse hematopoietic cells leads to a reduction in inflammatory intestinal T cells. Here we will define the cell types requiring this signaling pathway for induction of inflammatory T cells in the intestine, and the upstream receptors involved. We will characterize how the pathway controls cell behavior to promote inflammatory T cell accumulation and determine the importance of the pathway in a mouse colitis model. These studies will provide a foundation for defining the contribution of the signaling pathway to human IBD and may lead to the identification of new avenues for therapeutic intervention to treat this condition.

Abstract or Project Description

Our skin and gut house multitudes of bacteria that influence our health via interactions with key immune sentinel cells that engulf these microbes and respond dynamically to their signals. Previously we have had to rely heavily on animal models to try to decode this language between our immune sentials and the bacteria they sense, because we have lacked to tools to meaningfully capture the relevant information from human tissues. To overcome this hurdle we have recently developed a novel single-cell genomic method for simulatenously capturing and sequencing DNA from both these immune sentinel cells and the bacteria they contain, therby providing us with an unprecendented view into the nature of these bacteria-immune cell interactions. By applying this novel approach to samples of healthy human skin and gut, we hope to shed new light on how helpful and harmful bacteria are sensed at these barrier tissues, how the immune system decides when (and what) to attack, and the molecular and cellular cues that guide these decisions. These studies will transform our understanding of bacterial influences on our health and set the stage for future work to interrogate their role in specific human diseases such as Inflammatory Bowel Disease.

Abstract or Project Description

Clinical decision making in ulcerative colitis relies on practice guidelines and physician experience, but both have limitations. Guidelines offer broad advice that may not apply to individual patients while physician experience is subjective and error prone. Dr. Rudrapatna will address these limitations using reinforcement learning, a type of artificial intelligence that learns to make optimal decisions over time. Reinforcement learning has successfully been used in autonomous driving and it will now be adapted and applied to ulcerative colitis.

Abstract or Project Description

The intestinal immune system must maintain a delicate balance between harmless bacteria in the gut and immunity against dangerous pathogens. Dysregulation of this balance can lead to Inflammatory Bowel Diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease. Many treatments for IBD focus on blocking inflammation and fail to repair damaged tissue and restore the integrity of the tissue. We have identified a long non-coding RNA that is only expressed in the colon. When this RNA is present the tissue is healthy and functional. In patients with ulcerative colitis however, the levels of this lncRNA decrease. To model this state, we generated mice lacking this lncRNA and like patients with UC, these mice develope colitis. The lncRNA localizes to the mitochondria in cells of the healthy colon. When the lncRNA is lost, the mitochondria in the cells in the colon are damaged, produce reactive oxygen species and damage colonic tissue. These findings provide new insights into how a lncRNA can help mitochondria work well to maintain homeostasis in the gut. These studies suggest new opportunities to restore tissue health by controlling the levels of this lncRNA.

Abstract or Project Description

Mental health profoundly impacts inflammatory diseases of the body. This is particularly apparent in Inflammatory Bowel Disease (IBD), where stressful events in a patient’s life often enhance the severity of subsequent disease flares. Psychological stress is also strongly linked to bowel motility problems in IBD patients. How the state of the brain influences inflammation in the gut is a fascinating question that remains poorly understood.

In this study, we will explore the mechanisms of brain-gut communication that link psychological stress to IBD severity. Using several different mouse models of IBD, we have recently discovered a pathway that links stress perception by the brain to the enteric nervous system (ENS), and in particular glia cells that reside in the gastrointestinal tract. We will explore how this neuronal brain-gut connection exacerbates the inflammatory state in the gut. We will also determine whether the same pathway is active in IBD patients in the context of stressful life events.

Collectively, this work will improve our understanding of how the brain and the gut communicate during psychological stress. We hope that an improved understanding of how stress influences intestinal inflammation will ultimately facilitate harnessing the power of brain-derived signals in the treatment of IBD.

Abstract or Project Description

Therapies that help heal the lining of the intestines are needed in IBD care. These therapies are not currently available because it is not yet fully understood how the intestine repairs itself after an injury. Dr. Belle seeks to understand whether nerves of the intestines help orchestrate intestinal regeneration.

Abstract or Project Description

Knowledge of the intestinal microbiota has transformed medical science, but not the treatment of Inflammatory Bowel Disease (IBD). The microbiota is difficult to use clinically because current analytical methods provide outputs that are too complex to provide useful data during an acute IBD flare. To solve these issues, we have developed a novel methodology, “MicFly,” that allows us to “count” each type of bacteria present in the microbiota. Our method provides rapid, accurate, quantitative and simple measurements of the bacteria present in the microbiota and has the added benefit of being capable of identifying what genes are being expressed by each bacteria.

Clostridiodes difficileÊinfection (Cdiff;CDI) is common in IBD patients because the pre-conditions for CDI, low microbiome diversity and immunosuppression, are common outcomes of treatment. Discriminating CDI from an IBD flare can be difficult because Cdiff is commonly found in IBD patients but is only dangerous when it expresses a toxin. As an example of the efficacy of MicFly, we propose to demonstrate that the technique can identify the number of Cdiff bacteria and their toxin expression. We will also measure whether a Fecal Microbiota Transplant for Cdiff has been successful in reducing Cdiff toxin levels and restoring microbiota diversity.

Abstract or Project Description

A raw and compelling interdisciplinary work by UJDC and Choreographer Antoine Hunter exploring the experiences of Deaf children navigating the education system, pulling from interviews with Deaf students, educators and families.

Abstract or Project Description

Inflammatory Bowel Disease (IBD) comprises incurable chronic diseases of the gut which oscillate between periods of disease worsening (i.e. relapse) and relatively normal health (i.e. remission). Whilst current medicines often reduce this see-sawing problem, their effectiveness eventually wanes to the point where a large percentage of IBD patients still need hospitalisation and major surgery during their lifetime. Indeed, our current inability to cure IBD denotes that existing medicines do not tackle the root cause of IBD.

In this context, we have discovered that gut cells in IBD patients are much more prone to dying than gut cells in healthy patients. Remarkably, this shift towards exaggerated gut cell death also occurs in IBD patients who are in remission and experiencing a period of “normal health,” leading us to predict that excessive gut cell death is a root cause of IBD. In this project, we will aim to understand why gut cells in IBD patients are primed to die, and test whether correcting this molecular defect can achieve long-lasting remission.

Abstract or Project Description

Our gut is constantly exposed to environmental harms, such as bacteria and dietary products, among others. The epithelium layer of our intestinal tract, which is the most exposed to the external world, contains a variety of immune cells, which likely play an important role in patrolling and defending our intestine. However, how these cells protect epithelial cells and the host from pathogens and other insults is still poorly understood. We aim to better understand how a specific subset of intraepithelial immune cells, known as gd T cells, contributes to gut homeostasis. We found that these cells are highly decreased in Crohn’s disease (CD) patients, suggesting that they exert protective roles during disease. In addition, we found that they are heterogeneous and can crosstalk with either epithelial cells or other immune cells located deeper in the tissue. Herein, we plan to design functional experiments to better understand their role in the context of gut immune responses and how they affect surrounding epithelial or other immune cell types. In addition, we aim to identify if they derive from a common precursor or if they are highly diverse and whether this scenario is altered in CD.

Abstract or Project Description

“Native Seed Aflame (K)now” aims to deepen connections between traditional California Native knowledge holders and transform our collective relationship with fire from one of fear to one of respectful tending. Funds from a development support grant will be used to convene artists with fire stewards, parks officials and community members through fire-knowledge workshops and narrative skill shares.

Abstract or Project Description

Microbiota small molecules correlate with IBD pathogenesis, yet the molecular mechanisms behind remain elusive. We recently developed gene manipulation tools in multiple gut Clostridia commensals, and by mutating the responsible gene and mono-colonizing germ-free mice with the mutant, we can switch specific microbiota metabolites on/off in vivo and found that metabolites derived from Clostridia amino acid transamination, like branched short-chain fatty acids (BSCFAs) suppress intestine IgA plasma cells. Many microbiota-associated metabolites, including BSCFAs, are derived via microbial transamination of dietary amino acids and are highly abundant in the host. Multiple studies have shown that this group of microbial metabolites is significantly different between IBD patients and healthy humans. We hypothesize that microbiota metabolites from amino acid transamination mediate intestine immunity and inflammation. Herein we will apply Clostridium CRISPR-based toolsets to modulate these amino acid-derived metabolites in vitro and in vivo, investigate their effects on intestinal immunity and inflammation in germ-free and colitis mouse models, and look into clinical samples to determine if their levels are positively correlated with disease severity in IBD patients. Our findings will uncover previously unknown molecular mechanisms behind microbiome-IBD correlation and facilitate the identification of new therapeutic targets and new biomarkers for IBD prevention and treatment.

Abstract or Project Description

Professional Learning & Administrative Costs to attend Big Sky Literacy Conference and The Reading League Conferences in 2024.

Abstract or Project Description

To support the development and outreach of Yu Ming’s preschool program.

Abstract or Project Description

The Rest and Care Award is a one-time, invite-only program for current and past Education and Arts nonprofit grantees, offering six-week sabbaticals with pro-rated salary, benefits, leave expenses and organizational support, recognizing the dedication and resilience of leaders in our grantee community. Z Space Studio is a multifaceted performance space, theater production company and community arts hub. Executive Director Shafer Mazow has led the organization for four years.