Single cell transcriptome profiling to define cell types in brain nuclei controlling bladder function

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Overall - Abstract The goal of this Developmental Center for Interdisciplinary Research in Benign Urology is to bring together a team of world-class neuroscientists and benign urology researchers at the Beth Israel Deaconess Medical Center who will collectively undertake a scientific project, develop an educational outreach program and build a Center website in order to provide an invaluable resource for the urology community. The scientific project will use a state of the art technique, single cell RNA-seq (scRNA-seq), to perform simultaneous transcriptome profiling of thousands of neurons from the pontine micturition center-locus coeruleus (PMC-LC) and ventrolateral periaqueductal gray (PAGVL) brain regions. These brain regions play a critical role in controlling bladder filling and voiding. The resulting RNA expression profiles will identify the neuron subpopulations in these two crucial regions. To determine which of these subpopulations are most engaged in controlling the bladder the project will: 1. Determine which subpopulations project from PMC-LC to sacral cord and receive PAGVL input, and which PAGVL neurons project to PMC-LC and receive sacral cord input. 2. Determine which subpopulations alter their RNA expression patterns in response to a model of polyuria. Neuron subpopulations most likely to control the bladder will be studied by developing mouse lines which selectively express Cre recombinase in them, permitting us to define their functional role in normal mice and mice with disorders of bladder function (e.g. brain degeneration or prostate-induced chronic urethral obstruction). The Center will supplement and leverage the scientific project by engaging the expertise of all team members in educational outreach efforts designed to enhance the profile and understanding of benign urological disease research. The scientific efforts will be supplemented by 1) an active seminar program featuring invited outside speakers, 2) the training of 1 - 2 summer research undergraduates each year in uro-centric projects, 3) a regularly scheduled internal Center `lab' meeting for key personnel to present their progress/problems to the entire group, 4) an end-of-year retreat after the first year of funding is complete of Center investigators and 5) a day long symposium titled `New Frontiers in NeuroUrology' featuring both BIDMC Center participants, other Harvard neuroscientists and at least one invited external keynote speaker that will take place at the end of year 2 of funding. The retreat and the capstone symposium will be advertised broadly to the benign urology research community. All of these research and educational initiatives will be advertised on and made broadly accessible through a Center website to be built and run by the Administrative Core Director. This website will ultimately host an interactive curated neural atlas and transcriptome database with interpretive material, available for the broader community to utilize and download. This resource will permit targeted investigations of the neural underpinnings of numerous benign urological diseases.