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Abstract or Project Description

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

Abdominal pain, discomfort, and cramping are symptoms commonly experienced by individuals who suffer from inflammatory bowel disease or inflammatory bowel syndrome. Our conscious perception of gastrointestinal pain begins when sensory nerve fibers in the gut are activated or sensitized by chemical agents that we ingest, or that are produced by inflammation, stress, or bacteria. While some of these noxious chemicals interact with sensory nerve fibers directly, others first activate specialized cells, called enterochromaffin (EC) cells, that reside within the gut lining and communicate with sensory nerve endings to transmit pain signals to the brain. We are interested in learning more about the properties of EC cells, how they communicate with sensory nerve endings in the gut, and how this interaction initiates or exacerbates abdominal pain and/or cramping in the setting of inflammation or other insults to the gastrointestinal tract. We also want to know if this communication is bidirectional – that is, do nerve fibers ‘talk back’ to EC cells to regulate their activity or lifetime within the gut? By answering these and related questions, we hope to discover key molecules and mechanisms that contribute to gastrointestinal pain and may therefore represent novel targets for drugs intervention.

Abstract or Project Description

Fecal Microbial Transplant as a therapeutic modality for ulcerative colitis is effective in approximately 40% of patients. Trials of FMT offer the opportunity to identify the specific microbial functions and strains that promote disease remission and to develop more refined, high potency interventions comprised of groups of microbial strains that increase treatment efficacy. Microbes naturally exist as networks of functionally synergistic organisms whose collective activities modulate host immunity. We propose to identify mucosal-associated microbial functional gene networks encoded by transcriptionally active strains that promote resolution of colonic inflammation in FMT-responsive UC patients. Strains encoding these genes will be identified, isolated, genotyped and phenotyped and used to reconstruct communities of microbes that promote disease remission in human populations. These efforts aim to enable development of a microbial compounding pharmacy from which highly characterized synergistic strain compendiums may be formulated and tested for their capacity to reassemble, become transcriptionally active and promote resolution of colonic inflammation in pre-clinical humanized germ-free mouse models of colitis. Thus, we aim to leverage findings from FMT trials of UC patients to develop functionally defined and quality controlled microbial therapeutics for pre-clinical efficacy testing and ultimately, for tailored treatment of ulcerative colitis.

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

Post-transcriptional modifications of mRNA have emerged as a central mechanism to control genetic information flow. N6-methyladenosine (m6A) is the most abundant post-transcriptional modification in eukaryotic mRNAs. It is known that m6A methylation directs mRNAs to distinct fates for differential processing, translation and decay in various biological processes; however, the role of m6A methylation in intestinal physiology is unknown. We have sought to understand the role of m6A methylation in intestinal biology by genetically deleting METTL14, a core subunit of m6A methyltransferase. Mice with METTL14 deletion in gut epithelial cells suffered severe growth retardation and high premature mortality with aberrant intestinal structure. The objective of this project is to understand how epithelial m6A methylation regulates intestinal development. We will assess the effect of gut epithelial METTL14 deletion on intestinal morphogenesis, epithelial cellular diversity and cell type distribution in mice, as well as on the formation and structure of gut epithelial organoids in culture. We will identify METTL14-targeted transcripts and pathways in each cell population that are involved in intestinal morphogenesis, particularly those involved in the control of intestinal stem cell self-renewal and differentiation. We will also assess the effect of METTL14 deletion on the structure and composition of gut luminal bacteria.

Abstract or Project Description

Trillions of microorganisms line our intestine and play essential roles in human health. Our immune system needs to ignore these microorganisms, but be capable of attacking harmful bugs that enter the body. When this delicate balance goes wrong, inflammatory bowel disease (IBD) can occur. Understanding the molecules and pathways that control the gut immune system in health, and how these malfunction in IBD is crucial for identifying new targets for potential treatment.

Our previous work in mice identified a crucial anti-inflammatory pathway in the gut, showing that a molecule controlling the activation of a key regulator of the immune system (called TGF-beta) is critical in preventing intestinal inflammation. Our new work now shows that this anti-inflammatory pathway is present in humans, specifically on immune cells called monocytes and macrophages, but is completely absent in IBD patients.

Our proposal aims to determine why this protective pathway is missing in patients with IBD, by identifying molecular and genetic factors that are important in controlling its function. By understanding how this important anti-inflammatory pathway is regulated, we hope to identify potential ways of preventing or reversing it being switched off in patients with IBD.

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

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

To support the full-time art teacher whose annual compensation is $69,000 this academic year.

Abstract or Project Description

Crohn’s disease is an inflammatory bowel disease associated with significant morbidity. While the etiology is incompletely understood, alterations in intestinal microbiome composition and immune regulation play prominent roles in disease pathogenesis. Dietary therapies, including exclusive enteral nutrition, have been demonstrated to have favorable effects on disease activity but are limited by poor tolerability, high cost and logistical challenges. Other dietary strategies have been incompletely studied. Therefore, prospective studies on the impact of specific dietary interventions on disease activity, including microbiota composition, immunophenotype and biomarkers represent an unmet need. Time-restricted feeding is a form of intermittent fasting which has been shown to have anti-inflammatory effects in several conditions and is a no-cost and easy-to-implement intervention. This study will investigate the impact of a 4-week trial of time-restricted feeding on clinical disease activity, inflammatory and metabolic markers, the intestinal microbiome and immune cell composition in patients with mild-to-moderate Crohn’s disesae. Patients will undergo baseline clincal, nutritional and biochemical assessment prior to a 4-week intermittent fasting regimen for 16 hours daily. Longitudinal changes within the intestinal microbiome, inflammatory markers, and lymphocyte immunophenotype will be assessed before, during and post-intervention.

Abstract or Project Description

Sycamores, formerly known as Hathaway-Sycamores Child and Family Services, has been dedicated to supporting individuals and families in Southern California for over a century, offering vital care and services during challenging times. With a rich history dating back to 1902, Sycamores continues to provide innovative and impactful behavioral health programs, positively affecting over 18,000 lives annually,

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.

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

An immersive multimedia public performance project that employs interactive technologies to imagine possible futures in the era of climate change. Led by artist Tiare Ribeaux and ZERO1, TransGenesis brings together members of the Bay Area queer/People of Color arts and environmentalist communities as collaborators to collectively re-imagine our relationship to the environment and each other.

Abstract or Project Description

Uplifts the experiences of individuals affected by incarceration through an ensemble cast including former inmates. Premiering as part of AfroSolo Arts Festival’s 25 year anniversary.

Abstract or Project Description

Examines the devastating impact of the crack epidemic both locally and nationally. The project highlights the intergenerational trauma experienced by communities and explores intersections between the crack epidemic, the effect of natural disasters on communities of color and the current opioid epidemic.

Abstract or Project Description

AnnieCannons Inc. is a nonprofit organization that provides technical training and job opportunities in software development to individuals who have experienced human trafficking or other forms of exploitation, empowering them with valuable skills for economic independence and social reintegration.