Defining a novel transcriptional regulator of intestinal health and inflammation - Project Summary/Abstract The gastrointestinal tract is colonized by trillions of normally beneficial microbes (termed the microbiota), as well as serves as an entry site for pathogens. Therefore, the intestinal immune system must remain tolerant to foreign non-harmful stimuli meanwhile provide protection against infections. Accumulating evidence indicates that a dysregulated immune response in the intestine is causally associated with infectious, inflammatory, and metabolic diseases, such as inflammatory bowel disease (IBD). Despite these advances, the cellular and molecular mechanisms controlling protective versus inflammatory properties of immune responses within the intestine remain incompletely defined. The long-term goal of the candidate is to investigate how diverse immune and stromal cells are regulated to promote health and homeostasis in the mammalian intestine. The candidate’s recent work identified a novel transcription factor that is expressed by group 3 innate lymphoid cells (ILC3s) and specifically restrains the proinflammatory properties of ILC3s to promote intestinal health and protect against inflammation (Zhou et al., Nature, 2022). Based on this and new preliminary data, the candidate hypothesizes that this transcriptional regulator is an essential immune modulator limiting tissue inflammation and promoting intestinal health by acting across distinct cell types. The objectives of this proposal are to understand the regulation and functions of this transcription factor in intestinal health and inflammation across distinct cell types. Aim 1 will identify the direct targets of this transcription factor and how it regulates intestinal immunity. Aim 2 will investigate its functional significance in inflammation and dissect the molecular mechanisms by which it controls intestinal inflammation. Aim 3 will determine the upstream signals that modulate expression of this transcription factor, assess the impacts of intestinal inflammation on gene expression, and interrogate the physiological consequences of these context-dependent expression alterations in intestinal health and inflammation. The results from this proposal will advance our understanding of essential pathways that shape mucosal immunity and impact the pathogenesis of IBD, which could provoke the development of novel therapeutic strategies targeting this transcriptional regulator or downstream mediators in inflammatory disorders of the gut. Career goals of the candidate are to become an independent investigator at an academic institute studying the cellular and molecular mechanisms that promote intestinal health. To fulfil these scientific and career goals, the candidate has support from a multidisciplinary advisory team with extensive experience on areas related to the proposed research and mentoring trainees to independence. The candidate has developed a plan to acquire necessary technique skills, advance scientific writing and communication skills, and enhance laboratory management and mentoring abilities during the K99 phase. This K99/R00 Award will permit an outstanding training opportunity, allow the candidate to successfully complete the proposed novel research, and flourish as an independent scientist focusing on mucosal immunity and gastrointestinal health.
