Atlas of autonomic and neuromodulatory lineages in the developing lower urinary tract

项目概要 下尿路 (LUT) 的正常功能需要协调神经元活动以允许膀胱 充盈以储存尿液，然后收缩膀胱以在适当的时间排空 和地点。尽管人们对 LUT 的神经解剖学和成熟电路了解很多， 对于不同物种的分子组成、发育和出生后成熟知之甚少。 调节膀胱收缩力的神经元亚型。目前我们缺乏以下受体表达的目录 不同类型的盆腔神经节神经元可用于研究这些关键神经元如何到达 它们的目标是不同的 LUT 器官或手术损伤情况下的直接再生努力。更少的是 了解尿道化学感应刷细胞和副神经元的分子组成 定位于调节 LUT 收缩性。这些细胞含有高水平的神经递质，因此可以 作为神经调节剂，刺激膀胱因感染或机械拉伸而收缩。 了解盆腔神经节运动神经元与这些神经调节细胞之间的联系 将能够对膀胱敏感和收缩性对感染的反应进行详细的机制研究， 炎症或尿液成分。 GUDMAP Atlas 项目的总体目标是填补这些空白 知识，以便进行未来的机理研究。提出了四个具体目标：(1) 编译发育过程中盆腔神经节神经元以单细胞分辨率表达的基因图谱 和出生后的成熟； (2)绘制尿道神经调节细胞的首次出现和分布图 在小鼠的发育过程中； (3) 鉴定尿道神经调节细胞亚群的遗传标记 通过RNA测序； (4) 生成神经末梢之间详细的时空图 神经调节细胞和感觉或自主盆腔神经节神经元。这些研究将产生新颖的 GUDMAP 数据库当前缺少的信息。我们的结果将总结在图表中 GUDMAP 网站上的教程图和确定的基因集将加快以下领域的比较研究： 人体组织。因此，研究界将能够研究特定细胞的功能 使用细胞类型和基因特定方法进行类型和测试假设。

PROJECT SUMMARY Normal function of the lower urinary tract (LUT) requires coordination of neuronal activities to allow bladder filling for urine storage later followed by bladder contraction to accomplish emptying at an appropriate time and place. Despite the fact that much is known about the neuroanatomy and mature circuitry of the LUT, relatively little is known about the molecular composition, development and postnatal maturation of distinct neuron subtypes that regulate bladder contractility. At present we lack a catalog of receptors expressed by different types of pelvic ganglia neurons that could be used to investigate how these critical neurons reach their targets in different LUT organs or direct regenerative efforts in cases of surgical damage. Even less is known about the molecular makeup of chemosensory brush cells and paraneurons in the urethra that are positioned to modulate LUT contractility. These cells contain high levels of neurotransmitters and thus can act as neuromodulators that stimulate bladder contraction in response to infection or mechanical stretch. Knowledge of the connections between motor neurons in pelvic ganglia and these neuromodulatory cells would enable detailed mechanistic studies of bladder sensitization and contractility in response to infection, inflammation or urine composition. The overall goal of this GUDMAP Atlas project is to fill these gaps in knowledge so that future mechanistic studies can be pursued. Four Specific Aims are proposed: (1) compile an atlas of genes expressed by pelvic ganglia neurons at single cell resolution during development and postnatal maturation; (2) map the first appearance and distribution of urethral neuromodulatory cells during development in the mouse; (3) identify genetic markers for subsets of urethral neuromodulatory cells by RNA-seq ; (4) generate a detailed spatial and temporal map of nerve terminals between neuromodulatory cells and sensory or autonomic pelvic ganglia neurons. These studies will generate novel information that is current lacking from the GUDMAP database. Our results will be summarized in diagrams and tutorial maps on the GUDMAP site and the gene sets identified will expedite comparative studies in human tissues. As a result the research community will be able to investigate the functions of specific cell types and test hypotheses using cell type and gene specific approaches.