Defining the role of CRH-expressing neurons in Barrington's Nucleus (BN) and Characterizing the other neuronal subpopulations in BN

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PROJECT SUMMARY/ABSTRACT The candidate for this K08 Mentored Clinical Scientist Research Career Development Award aims to become an expert and leader in the field of neuro-urology, specifically on furthering our understanding of the brain-bladder control of volitional voiding. Lower urinary tract symptoms (LUTS) and disorders of voiding are among the most common reasons for referral to the urologist and affect ~20% of school-aged children and >40% of adults over 40 years old. Despite this prevalence, the specific neuronal populations that control voiding remain largely unknown which limits therapeutic options. Recent advances in neuroscience, genomics and bioinformatics will now allow study of specific neuronal subpopulations and characterization of the cellular heterogeneity inherent to all brain and brainstem nuclei. The proposed research in this grant will be performed in primary mentor Dr. Steven Zderic’s laboratory using mice. Aim 1 will determine the effects of long-term activation of one specific neuronal subpopulation in the pontine micturition center (i.e., Barrington’s nucleus, BN) on voiding function. These specific neurons express corticotropin-releasing hormone (CRH) and these neurons in preliminary studies were shown to inhibit voiding, thus activation of these neurons is expected to cause infrequent voiding and lead to bladder wall remodeling from chronic holding of urine. Aim 2 will identify the time and temporal pattern of firing of these CRH-expressing BN neurons in relation to volitional voiding using fiber photometry in freely moving mice. Aim 3 will utilize single cell RNA-sequencing techniques to identify and characterize the neuronal subpopulations that reside in and around BN. The first two aims will help define the role of BN CRH-neurons and potentially create a novel murine model of bladder wall remodeling, while aim 3 will lead to the identification of novel neuronal subpopulations for future study which could potentially lead to new therapeutic targets for LUTS and voiding disorders. The candidate brings to this proposal his experience studying voiding disorders both from a clinical and basic science standpoint. This career development proposal aims to provide the candidate with required additional training that leverages the resource-rich environment of the Children’s Hospital of Philadelphia and University of Pennsylvania. The candidate will be guided by an experienced mentoring team at CHOP [Dr. Zderic – Direct of Pediatric Urology Research; Dr. Seema Bhatnager – Associate Professor, neuroscientist; and Dr. Deanne Taylor – Director of Bioinformatics]. An Advisory Committee of internationally recognized leaders will provide content expertise and career counseling to ensure the candidate has a successful transition to independence as a surgeon-scientist. All together this research and training plan will provide the candidate with a foundation in advanced neuroscience, genomic, and bioinformatics necessary for achieving his long-term goals of understanding how specific brain and brainstem neuronal populations control voiding and finding ways to translate this knowledge into clinical improvement for patients with LUTS and voiding disorders.