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: 9378290
• 负责人: E Michelle SOUTHARD-SMITH
• 金额: $ 32.5万
• 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/9378290
• 关键词: Acetylcholine; Adult; Afferent Neurons; Appearance; Atlases; Autonomic ganglion; Bladder; Bladder Control; Blood Vessels; Brush Cell; Cataloging; Catalogs; Cell Separation; Cells; Colectomy; Collaborations; Communities; Comparative Study; Complement; Cryoultramicrotomy; Cues; Data; Data Set; Databases; Development; Disease; Enterochromaffin Cells; Epithelium; Functional disorder; Future; Ganglia; Genes; Genetic Markers; Genetic Transcription; Genital system; Goals; Growth; Human; 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; Resources; Sampling; 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; human tissue; mature animal; member; nerve supply; neuroregulation; novel; postnatal; public health relevance; receptor; regenerative; repaired; response; 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 下尿路（LUT）的正常功能需要神经元活动的协调， 随后进行膀胱收缩以在适当的时间完成排空 和地点。尽管我们对LUT的神经解剖学和成熟电路已经了解得很多， 相对而言，人们对不同的哺乳动物的分子组成、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，我们缺乏一个受体表达的目录， 不同类型的骨盆神经节神经元，可用于研究这些关键神经元如何达到 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。更不是 已知尿道中化学感受刷细胞和paradrons的分子组成， 定位成调节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，刺激膀胱收缩以响应感染或机械拉伸。 盆神经节运动神经元与这些神经调节细胞之间联系的知识 将能够对膀胱敏感性和对感染的收缩性进行详细的机制研究， 炎症或尿成分。GUDMAP Atlas项目的总体目标是填补这些空白， 知识，以便将来可以进行机械研究。提出了四个具体目标：（1） 编制一份发育过程中盆神经节神经元单细胞分辨率基因表达图谱 尿道神经调节细胞的首次出现和分布 （3）鉴定尿道神经调节细胞亚群的遗传标记 通过RNA-seq ;（4）生成神经末梢的详细空间和时间图， 神经调节细胞和感觉或自主盆神经节神经元。这些研究将产生新的 这是目前缺乏从GUDMAP数据库的信息。我们的结果将用图表来概括 GUDMAP网站上的教程地图和确定的基因集将加快比较研究， 人体组织因此，研究界将能够研究特定细胞的功能， 类型和测试假设使用细胞类型和基因特异性的方法。