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Abstract or Project Description

Abstract or Project Description

IBD patients have increased chances of developing colorectal cancer. Additionally this specific form of colon cancer is very difficult to treat. Despite numerous efforts we still do not fully understand the relationship between intestinal inflammation and the increased chance for colon cancer development. Understanding this will allow us to develop more specific and targeted prevention measures. Recently, a 3D culturing system of intestinal organoids (“”miniguts”” in a dish) has been developed. By clonally expanding single intestinal stem cells, we can obtain sufficient DNA to study DNA damage caused by or associated with chronic inflammation. The nature of this DNA damage will serve as a “”smoking gun”” that allows us to identify major forces causing IBD-associated colorectal cancer and thus to develop specific preventive therapies

Abstract or Project Description

Eicosanoids are signaling molecules that contribute to both the development and resolution of inflammation. Inflammasomes are immune sensors that help to trigger immune responses to infection. Tuft cells are specialized cells of the intestinal lining that are important during infection with parasitic worms. Eicosanoids and inflammasomes have been separately implicated in IBD, although the underlying mechanisms remain unclear. The role of tuft cells in IBD has not been studied. We hypothesize, based on results from our previous research, that tuft cells are a primary source of eicosanoids when inflammasomes are triggered in the intestinal lining. We plan to use specialized tools obtained or generated by our research groups to confirm this hypothesis and to assess how this unique convergence of tuft cells, inflammasomes, and eicosanoids might contribute to IBD. Drugs to modify the effects of eicosanoids are already available, thus our findings could have immediate clinical implications.

Abstract or Project Description

Although there are many drugs available for the treatment of IBD, most patients do not respond long-term to any one drug. One possible reason is that the condition we call “IBD” likely represents many distinct diseases, rather than simply just ulcerative colitis and Crohn’s disease, and each subtype may require a different treatment. Here we will address this problem by using a suite of state-of-the-art laboratory techniques that will allow us to study the genetic instructions (RNA) of thousands of individual cells sampled from the intestines of patients with IBD. Using bioinformatic methods, we will use this information to classify IBD into different diseases, which may help us to determine how best to treat each subtype. We also hope to discover new molecules that are involved in causing IBD, an important first step to developing new treatments for IBD

Abstract or Project Description

Inflammatory Bowel Disease (IBD) is characterized by chronic intestinal inflammation, which causes damage to the intestinal epithelium. This inflammatory response in the small and large bowel is thought to be initiated by interactions between genes, environment, and microbes, which reside in the gastrointestinal tract. However, the mechanisms by which environmental factors modulate susceptibility to IBD remain incompletely understood.

We hypothesize that changes in the host environment alters the susceptibility of intestinal tissues to damage, which is mediated by the microbes and the host immune response against them. Our preliminary data suggest that one such environmental factor is host metabolism, which regulates the expression of tissue tolerance programs to mitigate tissue damage caused during colitis. In this proposal, we will develop a new experimental framework to study intestinal tissue tolerance and identify the underlying mechanisms by which host metabolism protects tissues from microbe- and immune-mediated damage. A better understanding of these mechanisms will provide alternative targets and strategies for therapeutic intervention in IBD.

Abstract or Project Description

The gut is composed of many cell types that contribute to its complex functions and ability to adapt to changing conditions associated with diet, lifestyles and the environment. Each of these factors can affect the health of the gut and contribute to intestinal disease such as inflammatory bowel disease and intestinal discomfort and pain. Many current therapies target the immune system even though the gut contains many other types of cells which are crucial for sensing chemical changes within the gut. Our UCSF team of basic and clinical scientists is exploiting modern and powerful tools to revisit important but rare cell types within the gut that communicate with the nervous system. We are using these tools to ask if a novel pathway regulates the number and function of these critical cells. Such knowledge could be leveraged to generate therapies for intestinal disorders, particularly those associated with inflammatory pain.

Abstract or Project Description

Environmental factors are thought to contribute to the development of a range of human diseases, including inflammatory bowel disease (IBD) and autism spectrum disorder (ASD). Interestingly, the incidence of IBD is higher in patients with autism, compared to those without. We propose that inflammation to which a developing embryo may be exposed in the maternal womb, could be an environmental risk factor linking autism and IBD.

We previously showed that a particular type of immune cells, Th17 cells, in mothers, promotes autism-like phenotypes in offspring, using a mouse model of inflammation-induced neurodevelopmental disorders (i.e. autism). Th17 cells, and the pathways that control them, are also implicated in IBD. We propose that prenatal, maternal inflammation, through Th17 cells both enhances autistic phenotypes and increases IBD susceptibility in offspring. Our work thus aims to elucidate the intricate connection between maternal inflammation, autism and IBD. In addition, this research will lay the foundation for future studies to identify novel therapeutics for treating maternal inflammation- induced IBD.

Abstract or Project Description

The gastrointestinal tract absorbs nutrients through the intestinal epithelium while controlling the resident bacterial community. A significant increase in the risk for inflammatory bowel diseases (IBDs) is associated with high cholesterol diets; dysbiosis, an imbalanced composition of gut bacteria, is an important hallmark of intestinal inflammation in patients with IBDs. However, the role of dietary cholesterol in shaping the commensal bacteria and in controlling the pathogenesis and development of IBDs has not been yet addressed at the molecular level. Using a novel in vitro tissue-engineered system, we will dissect dietary cholesterol/intestinal immune cells axis in a mechanistic fashion, uncovering the biochemical and cellular requirements for the cholesterol metabolism to locally regulate intestinal antibody secretion and shape intestinal commensal bacteria. By skewing the commensal composition in vivo with the use of antibiotics, we will model the degree of dysbiosis observed in patients with IBDs and we will reveal the molecular relationship between dietary cholesterol absorption, commensal bacteria and intestinal inflammation. Our proposed research has a high intrinsic translational value, as the identity of the commensal strains that can modulate cholesterol absorption and IgA secretion in health and disease could provide clinical alternatives to restore intestinal homeostasis through pharmacological or dietary interventions.

Abstract or Project Description

Inflammation is an integral part of immune defense against pathogens or tissue damage. However, inappropriate or prolonged inflammation has deleterious consequences and underlies many chronic diseases, especially inflammatory bowel diseases (IBD) like Crohn’s disease and colitis. Specialized immune sensors that reside inside the cell cytosol are of particular interest in IBD, because mutations in the genes encoding these cytosolic sensors are strongly linked to Crohn’s Disease. It is not well understood how these cytosolic sensors are exposed to their ligands, which are derived from bacteria residing outside of the cell, in the lumen of the gut. This study will investigate components and mechanisms that deliver bacterial products to the intestinal cell cytosol and thereby regulate inflammation and contribute to intestinal health. The goal of this study is to determine the mechanism by which microbial products reach the cytosol and trigger key cytosolic innate immune sensors, which are known genetic risk factors for developing IBD. This study will provide new insights into the mechanisms of activation of these cytosolic sensors, and may eventually lead to new ways to intervene in the pathogenesis of IBD.

Abstract or Project Description

Many genetic factors have been associated with increased IBD susceptibility. However, these only explain a fraction of the disease risk that an individual with such a predisposition experiences. Environmental factors have been proposed to work in combination with host genetics to cause IBD. Diet and the normally beneficial community of bacteria that live in the human intestine are candidate “environmental” factors. The industrialized world, in which IBD is more prevalent, has experienced reduced consumption of dietary fiber–a term used to represent a group of complex carbohydrates abundant in vegetables and grains. Humans cannot directly digest fiber, so it transits to the distal intestine and is digested by gut bacteria. We have shown that a lack of dietary fiber causes gut bacteria to turn to a different source of carbohydrates to survive: protective intestinal mucus, which normally forms a barrier that keeps bacteria at a “safe distance” from host tissue. We propose that chronic or transient reductions in fiber trigger gut bacteria to erode the mucus layer, bringing them into proximity with the host and causing disease flares. Support for our model will allow us to explore dietary therapies to prevent IBD occurrence by reinforcing the integrity of the mucus layer.

Abstract or Project Description

The incidence of Inflammatory Bowel Disease is increasing worldwide in lockstep with modernization and worldwide ‘Westernization’ of lifestyles. One of the most important aspects of Westernization for human health is the adoption of a diet high in fat and sugar and low in fiber. Relatively little is known about how dietary sugar specifically affects the incidence and severity of IBD, though increased intake has been associated with disease, and diets low in simple sugars have shown promise in combating IBD in the clinic. Our preliminary data has indicated that a short course of dietary sugar supplementation is sufficient to induce a lethal syndrome characterized by profound intestinal pathology in mice undergoing a common colitis protocol. Additionally we have associated increased sugar in the diet to population shifts in intestinal immune cells. Here we propose to study how sugar mediates changes to the immune system and colon resident bacteria and how they might lead to a breakdown of the intestinal epithelium. At the conclusion of this work we hope to define novel sugar-modified mechanisms of the intestinal immune response with the hope that these will aid in efforts to design diets for IBD patients that will reduce inflammation and disease flares.

Abstract or Project Description

Upward Scholars is a Latinx-led organization that provides adult immigrants the boost they need to move up the economic ladder through education and career development support.

Abstract or Project Description

Uses sign language, spoken text, dance, silence and music to present different Deaf women’s experiences of discrimination and abuse. The project seeks to bring awareness to the Deaf community who are often overlooked within the #metoo movement.

Abstract or Project Description

To support the short film “Van Annie.”

Abstract or Project Description

The Viking Future Foundation is a non-profit organization founded and operated by Edison High School alumni focused on providing support for Edison High in Stockton, CA. Rosie Cabanig Scholarship (formerly the Intellectual Acuity Award) is a scholarship recognizing students for quick and critical thinking and innovative solutions to improve their community.

Abstract or Project Description

The microbes that colonize the human intestine, collectively known as the gut microbiome, are critical players in many human diseases including IBD. Patients with IBD often have fewer different types of intestinal bacteria and an increase in certain types of bacteria associated with inflammation. In addition to bacteria, there are many viruses that live in the human gut. Small viruses called bacteriophages can infect the gut bacteria, causing substantial changes to bacterial populations. IBD patients have expanded populations of bacteriophages, which may play a role in disease. While bacteriophages are important in IBD, a critical hurdle is that our knowledge of the diversity of different phages, and which bacteria they infect, is extremely limited. We will use a new technique that allows us to look at single intestinal bacteria and carefully analyze the virus(es) that infect them. This will allow us to better understand the predator-prey relationships they share with bacteria. These studies will provide important insight into the complex interactions between bacteria and bacteriophages in the microbiome, and help us understand how and why these interactions are altered in IBD. Ultimately, these findings will facilitate development of probiotic and phage therapies for IBD.

Abstract or Project Description

According to the Montreal classification, ulcerative colitis (UC) disease scope varies from how much of the colon is affected, with lesser colon involvement called proctitis (E1) and extensive disease called pancolitis (E3). These differing extents impact rates of hospitalization, chance of colectomy, and cancer risk. When the extent of UC is limited (E1 or E2) there is always a sharp demarcation between macroscopically involved and uninvolved areas, although the underlying cause(s) of the clear separation between healthy and unhealthy tissues is unknown. We suspect that this line is determined by antibody-mediated damage to the nervous system that is connected to the colon, because nerves organization in bands around the colon is consistent with the disease pattern. This proposal will investigate this remarkable feature of UC, trying to determine the underlying causes, which may lead to a better understanding of the drivers of disease and progression.

Abstract or Project Description

The intestines are home to a community of not only bacteria, but also fungi, which are involved in several immune-mediated inflammatory diseases, including IBD. It is unknown how fungi appear in the intestine and whether they are part of the intestinal microflora early in life. In this project, we will explore whether gut fungi can be transferred from mother to the newborn. We will further study the composition of the fungal community in babies born to mothers with IBD to understand whether specific fungi can be transferred from the mother to the babies and potentially contributing to disease later in life.

Abstract or Project Description

The human intestine is home to trillions of bacteria of hundreds of different types, which are collectively referred to as the gut microbiota. Ideally, these microbes exist in a balanced state, where both microbe and man benefit from their presence. However, imbalances in the microbiota, which are referred to as ‘dysbiosis’, have been suggested to underlie the development of a variety of inflammatory diseases, including IBD. While there is broad consensus that microbiota composition in patients with IBD differs from healthy controls, it remains unknown whether this dysbiosis is a cause or effect of the imbalanced immune responses that underlie IBD development. Here, we propose to use a new model system to experimentally examine the effect of dysbiosis in patients with IBD on the gut immune system. These studies will reveal whether imbalances in the gut microbiota play a causal role in the immunological imbalances that trigger IBD development, and will reveal potential mechanisms by which we can correct dysbiosis to prevent or cure IBD in the future.