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

发育中的下尿路自主神经和神经调节谱系图谱

• 批准号: 9923344
• 负责人: E Michelle SOUTHARD-SMITH
• 金额: $ 11.47万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-17 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923344
• 关键词: Acetylcholine; Adult; Afferent Neurons; Appearance; Atlases; Autonomic ganglion; Bladder; Bladder Control; Blood Vessels; Brush Cell; Catalogs; Cell Separation; Cells; Colectomy; Collaborations; Communities; Comparative Study; Cues; Data; Data Set; Databases; Development; Disease; Enterochromaffin Cells; Epithelium; Functional disorder; Future; Ganglia; Genes; Genetic Markers; Genetic Transcription; Genital system; Goals; Growth; Hypersensitivity; Hysterectomy; Image; Immunohistochemistry; Incontinence; Individual; Infection; Inflammation; Irritants; Kidney; Knowledge; Label; Lower urinary tract; Maps; Mechanics; Mediating; Methods; Molecular; Motor Neurons; Mus; Natural regeneration; Nerve; Neuroanatomy; Neuromodulator; Neurons; Neurotransmitters; Operative Surgical Procedures; Organ; Organogenesis; Pattern; Pelvis; Physiological Processes; Population; Positioning Attribute; Process; Prostatectomy; Reagent; Research; Research Personnel; Resolution; Scientist; Sensory; Serotonin; Signal Transduction; Site; Spatial Distribution; Spinal Ganglia; Stretching; Synapses; Testing; Time; Tissues; Transducers; Transgenes; Transgenic Mice; Transgenic Organisms; Urethra; Urine; Vertebral column; afferent nerve; autonomic nerve; axon regeneration; base; cell type; cellular microvillus; density; fetal; gene complementation; human fetal sample; human tissue; mature animal; member; nerve supply; neuroregulation; novel; online resource; postnatal; public health relevance; receptor; regenerative; repaired; response; single-cell RNA sequencing; spatial relationship; transcriptome; transcriptome sequencing; urinary bladder neck; urologic

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.

项目摘要 较低尿路（LUT）的正常功能需要对神经元活动的协调以允许膀胱 填充尿液储存后，然后进行膀胱收缩以在适当的时间清空 和位置。尽管事实是关于LUT的神经解剖学和成熟电路知之甚少，但 关于分子组成，发育和产后成熟的相对鲜明的了解 调节膀胱收缩性的神经元亚型。目前，我们缺少由表达的受体目录 可用于研究这些关键神经元如何达到的不同类型的骨盆神经元神经元 它们在不同的LUT器官中的目标或在手术损伤的情况下进行直接再生努力。更少的是 关于尿道中化学体的刷子细胞和旁神经元的分子构成已知 定位可调节LUT收缩力。这些细胞包含高水平的神经递质，因此可以 充当神经调节剂，响应感染或机械拉伸而刺激膀胱收缩。 了解骨盆神经节中运动神经元与这些神经调节细胞的连接 将对感染响应膀胱敏化和收缩性的详细机械研究， 炎症或尿液组成。这个Gudmap Atlas项目的总体目标是填补这些空白 知识使未来的机械研究可以进行。提出了四个具体目标：（1） 在发育过程中编译由骨盆神经元在单细胞分辨率下表达的基因的地图集 和产后成熟； （2）绘制尿道神经调节细胞的首次出现和分布 在小鼠的发育过程中； （3）确定尿道神经调节细胞亚群的遗传标记 由RNA-Seq; （4）生成神经终端的详细空间和时间图 神经调节细胞，感觉或自主神经神经元神经元。这些研究将产生新颖 GUDMAP数据库中缺少当前的信息。我们的结果将在图中总结 Gudmap位点上的教程图和所鉴定的基因集将加快比较研究 人体组织。结果，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的类型和检验假设。