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Abstract or Project Description

Abstract or Project Description

Inflammatory Bowel Diseases (IBD) are a devastating group of heterogenous inflammatory diseases that share the fact that the host immune system attacks the intestinal tissue disrupting gut functionality. All therapies currently available, such as biologics, target immune mediators that support damage and inflammation. Although these therapies ameliorated the life of many IBD patients, they not always work or stop to work overtime, highlighting the urgent need to develop new therapeutic approaches. Here, we propose to complement therapeutic interventions aimed at decreasing immune attack and intestinal damage by identifying new strategies that can be utilized to favor gut repair. In particular, we identified a new transcriptional program in intestinal epithelial cells that can be harnessed to facilitate intestinal healing. In our application we propose multiple studies based on: i) mouse models of colitis to test new therapeutic approaches; ii) human and mouse organoids to mimic intestinal epithelial cell damage and repair; and iii) use of biopsies from IBD patients and analysis of large human datasets to translate our findings to IBD patients. Our studies will reveal new therapeutic targets and strategies aimed at fostering tissue repair. These new interventions can be utilized in conjunction with current anti-inflammatory therapies to facilitate gut healing, thus ameliorating the quality of life of IBD patients.

Abstract or Project Description

We currently lack cures for chronic intestinal diseases. Despite incredible advances in understanding and targeting inflammation that promotes diseases like Crohn’s and ulcerative colitis, many patients develop resistance to treatment, suggesting alternative disease drivers beyond immune cells and the inflammatory molecules they produce. While the gut has remarkable regenerative capacity due to specialized stem cells that can rapidly generate all mature epithelial cells, diseases may impact underlying structural cells called fibroblasts which typically guide epithelial cell regeneration.

Our research vision is to identify the root causes of inflammatory diseases in the human gut. Our work suggests that fibroblasts play a central role, and our experiments to date have developed a unique and simple way to test how fibroblasts work closely with inflammatory immune cells. The specific internal cellular wiring diagrams and external cellular communication systems responsible for the identity and variety of fibroblasts that exist in the gut remains elusive. Our project aims to realize an integrative research plan that bridges careful human observation, computation and mechanistic experimental models. Our group is fundamentally interested in determining whether and how fibroblasts store and propagate disease in intestinal tissues to develop cures for IBD.

Abstract or Project Description

Glucocorticoids are the mainstay treatment to quell acute flare events in the context of Inflammatory Bowel Disease. These steroids are taken systemically and have broad and long-lasting side effects. As a result, alternative, safer approaches are sought. We have recently discovered that proteins made by the gut microbiota found predominantly in healthy individuals trigger the same receptors. This suggests that these proteins may have therapeutic benefit. The proposed research aims to further our understanding of these interactions. We aim to test whether these proteins, when amended to the gut microbiome of mice with colitis, are sufficient to reduce inflammation. Our ultimate goal is to develop therapeutics for patients with IBD that perform the role of glucocorticoids and act locally on inflamed tissue in the gut.

Abstract or Project Description

The intestine exerts the vital function of maximizing nutrient uptake from the diet we ingest, being constantly exposed to external stimulation by food components. Alterations in the timing of food intake and diet composition have been associated with the development of immune-related intestinal dysfunctions, including IBD. However, despite its profound biological and clinical relevance, there is a major gap in our understanding of how intestinal immune health is affected by diet. Recently, we uncovered that gut neurons are activated by the diet, and they can control intestinal immune responses. The long-term goal of this proposal is to determine how the diet is sensed by these neurons that have immune regulatory properties. Our studies are expected to uncover dietary and neuronal therapeutic targets to gut disturbances associated with a dysregulation in local immune responses, including IBD.

Abstract or Project Description

Colonization of the infant gut by commensal bacteria profoundly influences immune development and can thus have significant long-term consequences: promoting durable tolerance to environmental antigens or driving IBD. Despite the importance of this process for health, how immune responses to the microbiota are regulated during early life remain a significant gap in our knowledge. We discovered that antibodies targeting gut bacteria are transmitted from mother to offspring via breastfeeding where they restrain neonatal immune responses to beneficial gut bacteria. Antibodies are specialized immune proteins that bind to foreign particles, including harmful and helpful microbes. Healthy humans and mice produce distinct flavors, or “isotypes,” of antibodies that serve different functions in immunity. We revealed that the maternal antibody isotype required to restrain neonatal inflammatory responses is IgG, an isotype that has only recently been identified to participate in gut health. Human breastmilk also contains IgG, and a key role for maternal antibodies in dampening gut inflammatory responses has been described in breastfed humans. Here, we will combine new mouse models with cutting-edge approaches to define the mechanisms by which breastmilk antibodies instruct the neonate to avoid harmful responses to beneficial gut bacteria. This work will advance our ability to manipulate immune responses to gut bacteria and thus aid in the development of therapies to effectively curb the development or severity of IBD.

Abstract or Project Description

Autoimmune diseases, including many Inflammatory Bowel Diseases (IBD), reflect a breakdown in immunological tolerance. The immune system is designed to respond to foreign molecules (nonself-antigens) while ignoring an organism’s own constituents (self-antigens). For T cells, much of this self-tolerance is learned during their maturation in the thymus, through either elimination of potentially self-reactive cells or their pacification. But how is the T-cell repertoire purged of cells that recognize antigens not encountered until after they migrate into the periphery? We recently discovered a novel mechanism for previewing peripheral antigens to maturing T cells: thymic mimetics. These amazing cells are molecular hybrids between a small group of thymic stromal cells and diverse peripheral cell-types, and were shown to promote immunological tolerance to the peripheral cell-types’ antigens. A mimetic cell-type that has drawn our attention is thymic goblet-cell mimetics. Goblet cells, prominent in the intestine, safeguard the organism from microbial invasion by secreting mucins to form a protective mucus layer. Individuals with IBD often have aberrant goblet-cell histology and/or anti-goblet-cell autoantibodies. The overall goals of this project are to determine whether and how thymic goblet-cell mimetics control intestinal self-reactivity in mice and whether at least some human IBDs have a similar etiology.

Abstract or Project Description

The immune system in the gut faces a unique challenge: it must rapidly attack harmful microbes while coexisting with trillions of beneficial bacteria that promote digestion and health. When this balance fails, the immune system can mistakenly attack harmless microbes, leading to pathologies such as IBD. Although scientists have identified rare immune cells that promote tolerance to beneficial bacteria, it remains unclear how such scarce cells orchestrate this process throughout the gut. We propose that the immune system solves this problem by organizing immune responses in space. Specifically, we hypothesize that immune cells called T cells route to different regions within gut-draining lymph nodes based on the strength of the signals they receive. T cells sensing harmless bacteria receive weaker signals and are guided into specialized regions that promote tolerance. Conversely, T cells sensing dangerous pathogens receive stronger signals and remain in inflammatory zones, enabling protective responses. This project will use advanced, high-resolution imaging to map how immune cells interact within lymph nodes under healthy and inflammatory conditions. By uncovering the spatial rules that separate tolerance from inflammation, we aim to understand why immune balance breaks down during IBD and identify new strategies for restoring immune regulation in the gut.

Abstract or Project Description

 
Major challenges in studying inflammatory disorders include establishing causality—distinguishing cellular and molecular changes in immune cells that drive disease from those that arise as secondary consequences of inflammatory tissue damage—and shifting from a focus on individual cell types toward understanding how groups of cells function as circuits within inflamed tissues. These challenges are particularly acute in IBD where it remains unclear whether breakdowns in the intestinal barrier initiate or result from inflammatory immune activation. Our proposed studies focus on an understudied intestinal epithelial cell lineage, microfold (M) cells, which sample and deliver luminal antigens to immune cells in the underlying tissue and act, therefore, as a key cell type in balancing barrier integrity and immune activation. We propose that M cells function as a component of a spatially organized cell circuit with regulatory T cells and antigen-presenting cells in the inductive subepithelial dome niche of Peyer’s patches. We will dissect the organization and function of this circuit using novel genetic tools and integrated multi-prong cutting-edge analyses in mouse IBD models, intestinal infection and homeostatic conditions. These studies will provide biological and mechanistic frameworks for a novel immune-epithelial cell circuit whose malfunction may contribute to intestinal inflammatory disorders. 

Abstract or Project Description

Inflammatory Bowel Diseases (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) are caused by environmental triggers and a dysregulated immune system. Interactions between certain bacteria, known as pathobionts, and the gut immune system contribute to IBD in animal models. However, we understand little of the types of pathobionts that might be influencing human IBD. This project aims to generate a humanized mouse model engineered with a human T cell antigen recognition system (VelociT mouse from Regeneron) and human gut microbiota. Establishment of a colitis model induced by microbiota-dependent immune dysregulation will mimic pathogenesis in human IBD patients. These mice can be used for identification of the yet unknown IBD-related pathobiont(s) and understanding how the pathobionts interact with the immune cells. One major advantage of our model is that the humanized mice express a diverse set of the HLA alleles which allows them to be matched to patients with the same HLA alleles, allowing for patient-specific analysis and potentially testing of personalized therapies in the future. This model will help investigate the triggers of human disease development and bridge the gap between animal models and clinical IBD research, contributing significantly to better understanding of IBD pathogenesis.

Abstract or Project Description

Proteins serve essential functions in all living things by performing the many tasks required to keep a cell, and an entire organism, alive and healthy. To perform their jobs properly, however, proteins must be told what to do, and the way that this is accomplished is through protein modifications that serve as microscopic work orders. When proteins are not properly told what to do, this can cause diseases like autoinflammation. Two such modifications, known scientifically as ADP-ribosylation and ubiquitylation, are intimately linked to human health, and accordingly have emerged as multi-billion-dollar therapeutic targets in diseases such as cancer and neurodegeneration. Though historically considered as separate work orders for proteins, we recently discovered that ADP-ribosylation and ubiquitylation function cooperatively through a process we call MARUbylation. Remarkably, we have found that factors controlling MARUbylation are dysregulated in Inflammatory Bowel Disease (IBD). As such, further discovery in this space brings immense potential for understanding and treating these debilitating diseases. Our interdisciplinary team includes world-leaders in ubiquitylation, ADP-ribosylation and intestinal inflammation, bringing together the expertise necessary to understand MARUbylation in IBD. From our proposed work, we expect numerous biological insights and translational discoveries to emerge, yielding transformative impacts on future IBD research and care.

Abstract or Project Description

The immune system plays a major role in chronic Inflammatory Bowel Diseases, yet not much is understood about the early events that lead to the exacerbated inflammation that increases the risk of developing them. This project explores the idea that past infections influence long-term intestinal responses to stress or injury. The intestine is densely innervated and contains its own complex nervous system, often referred to as the “second brain,” which continuously communicates with immune cells to regulate inflammation, barrier function and pain. We propose that temporary infections, even those that resolve without obvious tissue damage, can permanently alter these nerve cells, changing how they interact with the immune system and increasing susceptibility to chronic inflammation, leading to disease. We are studying how gut nerves and immune cells change over time following infection. We will identify long-lasting molecular changes in these cells and test how activating or inhibiting specific nerve cell populations affects intestinal inflammation. By uncovering how interactions between the gut’s nervous system and immune system shape long-term intestinal health, this work aims to reveal new pathways that could inform earlier diagnosis and lead to more targeted treatments for chronic inflammatory intestinal diseases.