Serotonin signaling in control of the Lower Urinary Tract

控制下尿路的血清素信号传导

• 批准号: 10063871
• 负责人: E Michelle SOUTHARD-SMITH
• 金额: $ 38.25万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063871
• 关键词: Adult; Affect; Afferent Neurons; Age; Anatomy; Apoptotic; Behavior; Biological Assay; Bladder; Bladder Control; Bladder Diseases; Bladder Dysfunction; Brain; Cell Proliferation; Cell Survival; Cells; Chronic; Congenital Abnormality; Cyclophosphamide; Defect; Development; Developmental Process; Disease; Elements; Exhibits; Fetal Development; Frequencies; Functional disorder; Ganglia; Gene Expression; Genetic; Health Care Costs; Healthcare Systems; Hyperplasia; Hypersensitivity; Immunohistochemistry; Implant; In Vitro; Incontinence; Individual; Inflammation; Inflammatory; Interstitial Cystitis; Intervention; Intestines; Knockout Mice; Knowledge; Lead; Lower urinary tract; LoxP-flanked allele; Maps; Mediating; Molecular; Motor; Motor Neurons; Mus; Mutant Strains Mice; Mutation; Myofibroblast; NDRG1 gene; Nerve; Nervous system structure; Neural Crest; Neuroendocrine Cell; Neurogenic Bladder; Neuroglia; Neuronal Differentiation; Neurons; Organ; Patients; Pelvis; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Predisposition; Process; Pump; Quality of life; Regulation; Role; Sensory; Serotonin; Serotonin Receptors 5-HT-3; Signal Pathway; Signal Transduction; Smooth Muscle; Spinal Ganglia; Spottings; Surveys; Tactile; Testing; Time; Up-Regulation; Urethra; Urinary Retention; Urine; Urologic Diseases; Urologist; Urothelium; Vertebral column; Work; bladder pain; cell fate specification; density; experimental study; gastrointestinal; inflammatory pain; loss of function; loss of function mutation; mouse model; mutant; nerve stem cell; nerve supply; neurodevelopment; novel; personalized medicine; postnatal; progenitor; receptor; repaired; response; segregation; serotonin receptor; stem cells; urinary bladder neck

PROJECT SUMMARY Normal function of the lower urinary tract (LUT) requires coordination of neuronal activity to allow bladder filling for urine storage followed later by bladder contraction to accomplish urine expulsion at an appropriate time and place. Deficiencies in the development of the neural elements that mediate bladder control can lead to problems in patients such as neurogenic bladder, incontinence, urinary retention, or bladder pain. These LUT diseases result in reduced quality of life for patients, increase healthcare costs, and burden the health care system. While we know that the sacral elements of the peripheral nervous system, which participate in regulation of these bladder processes, include dorsal root ganglion (DRG) sensory neurons and autonomic (motor) pelvic neurons, there are many gaps in our knowledge regarding how these neurons develop and how deficits during development lead to congenital defects in bladder control. By surveying gene expression during development of pelvic ganglia in mice we have identified up-regulation of serotonin receptors that are also expressed in sensory neurons of developing DRG. Mice with loss of function mutations in these serotonin receptors, specifically the serotonin type 3 receptor (5-HT3), have abnormal development of nerves in the bladder wall and later exhibit urinary retention. Our preliminary work in isolated cultures of sacral neural crest stem cells indicates that perturbations of 5-HT3 signaling disrupt neuronal differentiation. We postulate that the bladder deficiencies observed in 5-HT3 mutant mice occur not only as the result of hyper-arborization of developing nerve terminals that lack 5-HT3 signaling, but also as a consequence of altered cell fate specification leading to imbalances among types of developing DRG and pelvic ganglia neurons. Cell fate specification is a novel function that has not previously been ascribed to 5-HT3 and has potential for pronounced impact on the types of neurons formed during development of bladder innervation. Such alterations in neuronal differentiation would predispose to deficiencies in bladder control and add to the potential for increased susceptibility to bladder pain. Three aims are proposed that will elaborate roles for 5-HT3 signaling during development of DRG and pelvic ganglia neurons that innervate the bladder. In Aim 1 we will use genetic and pharmacologic approaches to determine when 5- HT3 signaling is required to develop and maintain normal bladder innervation. In Aim 2 we will use Cre:LoxP lineage tracing studies in Htr3a gain and loss of function mutants to define the developmental processes and time periods that are affected by 5-HT3 signaling. In Aim 3 we will determine whether disruptions of 5-HT3 signaling during development increase vulnerabilty to bladder inflammatory pain. These studies will generate mechanistic knowledge of deficits in neural development that lead to bladder disease and will aid urologists in sculpting personalized therapies for patients.

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 充盈储存尿液，然后收缩膀胱，在适当的时间完成尿液排出 时间和地点。介导膀胱控制的神经元件发育缺陷可能会导致 导致患者出现神经源性膀胱、尿失禁、尿潴留或膀胱疼痛等问题。 这些 LUT 疾病会导致患者生活质量下降，增加医疗费用，并给患者带来负担 医疗保健系统。虽然我们知道周围神经系统的骶骨元件， 参与这些膀胱过程的调节，包括背根神经节 (DRG) 感觉神经元 和自主（运动）盆腔神经元，我们对于这些神经元如何 发育以及发育过程中的缺陷如何导致膀胱控制的先天性缺陷。通过测量 在小鼠盆腔神经节发育过程中的基因表达我们发现了血清素的上调 受体也在发育中的 DRG 的感觉神经元中表达。功能丧失的小鼠 这些血清素受体，特别是 3 型血清素受体 (5-HT3) 的突变，具有异常 膀胱壁神经发育，随后出现尿潴留。我们的前期工作 骶神经嵴干细胞的分离培养物表明 5-HT3 信号传导的扰动会破坏 神经元分化。我们假设在 5-HT3 突变小鼠中观察到的膀胱缺陷发生 不仅是由于缺乏 5-HT3 信号传导的神经末梢发育过度树枝化的结果，而且 由于细胞命运规范改变，导致正在发育的 DRG 类型之间不平衡 和盆腔神经节神经元。细胞命运规范是一种以前未被赋予的新功能 5-HT3，并且有可能对发育过程中形成的神经元类型产生显着影响 膀胱神经支配。神经元分化的这种改变会导致膀胱缺陷 控制并增加对膀胱疼痛的敏感性增加的可能性。提出了三个目标 将详细阐述 5-HT3 信号在 DRG 和盆腔神经节神经元发育过程中的作用， 支配膀胱。在目标 1 中，我们将使用遗传和药理学方法来确定何时 5- HT3 信号传导是发育和维持正常膀胱神经支配所必需的。在目标 2 中我们将使用 Cre:LoxP 谱系追踪研究 Htr3a 功能突变体的获得和丧失，以确定发育 受 5-HT3 信号传导影响的过程和时间段。在目标 3 中，我们将确定是否 发育过程中 5-HT3 信号传导的破坏会增加膀胱炎性疼痛的脆弱性。 这些研究将产生导致膀胱发育不良的神经发育缺陷的机制知识。 疾病，并将帮助泌尿科医生为患者制定个性化治疗方案。