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

定义巴林顿核 (BN) 中表达 CRH 的神经元的作用并表征 BN 中其他神经元亚群的特征

• 批准号: 9908084
• 负责人: Jason Philip Van Batavia
• 金额: $ 14.83万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908084
• 关键词: Adult; Advisory Committees; Affect; Basic Science; Bioinformatics; Biological Process; Bladder; Bladder Control; Bladder Dysfunction; Brain; Brain Stem; Cell Nucleus; Child; Childhood; Chronic; Clinical; Clinical Sciences; Conflict (Psychology); Corticotropin-Releasing Hormone; DNA biosynthesis; Data; Development; Development Plans; Disease; Ensure; Environment; Estrogens; Etiology; Fiber; Foundations; Funding; Future; Genetic Transcription; Genomics; Goals; Grant; Heart Atrium; Heterogeneity; In Situ; International; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Long-Term Effects; Mentors; Methods; Micturition Reflex; Modeling; Mus; Myosin ATPase; Nerve; Neurons; Neuropeptides; Neurosciences; Neurotransmitters; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Pennsylvania; Phenotype; Philadelphia; Photometry; Physicians; Physiology; Pontine structure; Population Control; Positioning Attribute; Prevalence; Publications; Rattus; Reproducibility; Research; Research Personnel; Research Training; Resources; Role; School-Age Population; Science; Scientist; Stress; Surgeon; Surgical Models; Techniques; Testing; Therapeutic; Time; Training; Translating; Universities; Urination; Urine; Urologist; Urology; Visualization; Vocational Guidance; Volition; base; calcium indicator; career; career development; experience; improved; in vivo; life-long learning; lower urinary tract symptoms; mid-career faculty; mind control; mouse model; new therapeutic target; novel; optogenetics; prevent; programs; receptor; saluretic; single-cell RNA sequencing; skills; social defeat; social model; social stress; success; targeted treatment; therapeutic target

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.

项目概要/摘要 K08 指导临床科学家研究职业发展奖的候选人旨在成为 神经泌尿学领域的专家和领导者，特别是在加深我们对脑膀胱的理解方面 控制自主排尿是最常见的下尿路症状（LUTS）和排尿障碍。 转诊至泌尿科医生的常见原因，影响约 20% 的学龄儿童和超过 40% 的成年人 尽管在 40 岁，控制排尿的特定神经元群仍然存在。 神经科学、基因组学和生物信息学的最新进展将限制治疗选择。 现在允许研究特定的神经元亚群和固有的细胞异质性特征 此项资助中拟议的研究将由主要导师 Dr. Steven Zderic 的实验室将使用 Aim 1 来确定长期激活一种特定物质的影响。 脑桥排尿中心（即巴灵顿核，BN）的神经元亚群对排尿功能的影响。 这些特定的神经元表达促肾上腺皮质激素释放激素（CRH），并且这些神经元处于初步研究中 被证明可以抑制排尿，因此这些神经元的激活预计会导致不频繁排尿并导致 目标 2 将确定长期憋尿的时间和时间模式。 使用纤维光度测定法在自由运动中激发这些表达 CRH 的 BN 神经元与意志排尿的关系 Aim 3 将利用单细胞 RNA 测序技术来识别和表征神经元。 居住在 BN 内及其周围的亚群。前两个目标将有助于定义 BN CRH 神经元的作用。 并有可能创建一种新型的膀胱壁重塑小鼠模型，而目标 3 将导致识别 用于未来研究的新神经元亚群，这可能会导致新的治疗靶点 LUTS 和排尿障碍候选人在本提案中提出了他研究排尿障碍的经验。 从临床和基础科学的角度来看，该职业发展提案旨在提供 接受过额外培训的候选人，以利用儿童医院资源丰富的环境 费城大学和宾夕法尼亚大学的候选人将受到经验丰富的指导团队的指导。 CHOP [Zderic 博士 - 儿科泌尿外科研究主任；Seema Bhatnager 博士 - 副教授， 神经科学家；和 Deanne Taylor 博士 - 国际咨询委员会主任]。 公认的领导者将提供内容专业知识和职业咨询，以确保候选人获得成功 总的来说，这项研究和培训计划将提供作为一名外科医生科学家的独立过渡。 候选人拥有实现他的目标所必需的先进神经科学、基因组和生物信息学基础 了解特定大脑和脑干神经群如何控制排尿和排尿的长期目标 寻找方法将这些知识转化为 LUTS 和排尿障碍患者的临床改善。