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Abstract or Project Description

Abstract or Project Description

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

Adherent-invasive Escherichia coli (AIEC), a pathogenic form of E. coli, is known to accumulate in the intestinal mucosa of patients with Crohn’s disease (CD). Although it is believed that AIEC exacerbates the disease by promoting intestinal inflammation, the precise mechanism underlying the abnormal expansion of AIEC in the intestinal mucosa remains largely unknown. We have found that AIEC prefers amino acids as a source of nutrients during inflammation and this nutritional preference is critical for its ability to gain a competitive edge over commensal non-pathogenic E. coli. Importantly, we have demonstrated that intestinal amino acids used by AIEC as nutrients are mainly derived from the diet and, therefore, the removal of certain key amino acids from the diet will prevent AIEC from thriving in the gut. In this study, we will aim [1] to clarify the role of dietary amino acid utilization by AIEC in the development of intestinal inflammation and [2] to unravel the mechanisms by which intestinal inflammation regulates the substrate preference of AIEC. A successful completion of this project is expected to result in the development of novel therapeutic strategies that will control the pathogen by restricting the availability of its preferred source of nutrients.

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

Intestinal scarring and thickening, also called fibrosis, afflicts >30% of inflammatory bowel diseases (IBD) patients, yet there is no cure and few treatment options. The fundamental processes underlying IBD-fibrosis are unknown, partly due to the absence of relevant animal models. This lack of basic understanding has prevented therapeutic development. Accordingly, our lab has developed a novel IBD-fibrosis mouse model. The community of microbes residing in our gut — the microbiota — strongly influences health and disease. IBD patients exhibit microbiota alterations, but it is unknown which specific microbial products incite pro-fibrotic host responses. Our data suggest that excessive quantities of a microbial small molecule secreted from intestinal bacteria, yersiniabactin, promotes intestinal fibrosis. Bacteria expressing yersiniabactin are over-represented in the intestines of IBD patients, which may drive fibrosis in these patients. In this proposal, we will characterize the pro-fibrotic immune cells induced by yersiniabactin, quantify secreted yersiniabactin levels, and determine how this microbial product causes fibrosis in a new mouse model of IBD. Together these studies will reveal host and bacterial mechanisms that promote fibrosis in IBD patients, and identify a potential drug target within the bacteria of our gut that could prevent fibrosis in IBD patients.

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

The rapid advancement in scientific innovations could easily seem like fiction to the casual observer. Each day seems to give new examples of a future in which we have the capabilities to radically transform human life in a laboratory. Embodying these concepts and pushing the boundaries of science are themes central to a growing field of art called Bio-Art (aka Sci-Art). Most often the relationship between medicine and art are about addressing the existential rather than using art to generate or answer hypothesis-based questions. This work is an exploration of the stool microbiome and illustrates how art can influence scientific discovery and be used to educate the public.

The short-term goal of the collaboration between a microbiologist and an artist was to develop a project that not only used biomedical research as art, but one that also advanced biomedical science. Specifically, using a combination of microbiological culture, immunology, mass spectrometry, photo-media and sculpture.

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

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

Youth Beat provides free digital media training to kids from some of the Bay AreaÕs lowest income neighborhoods. Their mission is to help inner-city kids get on a path that leads to success in college, career and life.

Abstract or Project Description

A large-scale multimedia community art project. This interdisciplinary site-specific work focuses on the dreams and aspirations of residents of Bayview-Hunter’s Point in San Francisco, as the neighborhood enters a period of economic and demographic transformation.

Abstract or Project Description

For a 9-month project to activate and enliven the “Block by Block” installation and its adjoining public space on San Francisco’s Market Street.

Abstract or Project Description

A collaborative work inspired by these two authors which seeks to illuminate contemporary social justice issues of race and cultural inequity.

Abstract or Project Description

A year long playwright residency and the premiere of Star Finch’s BONDAGE (working title), developed in the AlterLab 2015 residency.