Microbial regulation of intestinal tuft cell homeostasis

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Helminth infections and allergic diseases impact billions of individuals worldwide. While induction of type 2 immune responses are necessary for combatting helminth pathogens, inappropriate type 2 immunity triggers inflammatory and allergic conditions. Therefore, improved understanding of mechanisms that control type 2 immune responses are needed. The intestinal microbiota continually influence immune responses, and several studies have demonstrated that microbiota-derived factors dampen type 2 immunity. Intestinal tuft cells are specialized epithelial cells that are essential for sensing luminal signals and initiating downstream type 2 immune responses. My preliminary data indicate that the microbiota regulate tuft cell homeostasis and tuft cell-dependent type 2 immune responses in the intestine. Studies outlined in this proposal will directly test (i) how intestinal stem cells instruct tuft cell differentiation, and (ii) how commensal bacteria impact tuft cell-dependent type 2 immunity. Collectively, these studies will provide new insights into how the microbiota direct intestinal epithelial differentiation to instruct intestinal immune responses, and will guide novel microbiota-based approaches for investigating and treating type 2-driven intestinal diseases. My career goal is to establish myself as a successful investigator studying microbiota-regulated intestinal diseases. To progress towards this goal, I propose in this application to dissect interactions between the microbiota, epithelial cell differentiation, and mucosal immune responses. I will specifically concentrate on developing expertise in four new areas that will facilitate my transition to independence: 1) gnotobiotics and metagenomics, 2) type 2-driven murine disease models, 3) epithelial development and human intestinal organoids, and 4) chromatin and single cell analyses. My mentors, Dr. Alenghat and Dr. Wells, along with the exceptional scientific and intellectual environment at Cincinnati Children’s Hospital will enable me to utilize modern, innovative approaches in my research and collaborate with top investigators. Over the next five years, I fully anticipate that my background, in conjunction with the career development plan outlined in my application, will allow me to successfully carry out the proposed project. The mentoring and training I will receive will enable me to successfully transition to an independent research career directed towards fundamental advances in intestinal immunity, as well as innovative and targeted strategies for investigating microbiota-sensitive diseases.