Neural Crest Contributions to the Lower Urinary Tract

神经嵴对下尿路的贡献

• 批准号: 8658950
• 负责人: E Michelle SOUTHARD-SMITH
• 金额: $ 34.06万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658950
• 关键词: Ablation; Adult; Appearance; Autonomic ganglion; Birth; Bladder; Bladder Control; Bladder Diseases; Bladder Dysfunction; Cardiac; Cells; Child; Complication; Congenital Abnormality; Defect; Development; Developmental Process; Disease; Dose; Embryo; Endothelial Cells; Engineering; Enteral; Equilibrium; Etiology; Exhibits; Failure; Fluorescence; Functional disorder; Ganglia; Genes; Genitourinary system; Goals; Immigration; Immunohistochemistry; In Situ; In Vitro; Intestinal Motility; Intestines; Kidney Failure; Knowledge; Lead; Life; Lower urinary tract; LoxP-flanked allele; Maps; Mesenchyme; Mesoderm; Modeling; Mus; Muscle; Myofibroblast; Nerve; Nerve Fibers; Neural Crest; Neural Fold; Neural Tube Defects; Neural tube; Neurogenic Bladder; Neuroglia; Neurons; Organogenesis; Participant; Pathology; Patients; Pelvis; Pericytes; Peripheral; Peripheral Nervous System; Positioning Attribute; Process; Regimen; Reporter; Resolution; Role; Smooth Muscle; Somites; Spinal; Spinal Dysraphism; Stem cells; Structure; Systems Development; Tamoxifen; Testing; Thymus Gland; TimeLine; Tissues; Transgenes; Transgenic Organisms; Urethra; Urine; Urologist; body system; cell type; developmental genetics; fetal; migration; mouse model; mutant; nerve supply; neurogenesis; pressure; progenitor; public health relevance; research study; segregation; somitogenesis; trafficking; urologic

Our goal is to reveal developmental and genetic mechanisms that control formation of cell types from the neural crest (NC) in the lower urinary tract (LUT). NC progenitor cells form pelvic autonomic ganglia and peripheral glia along nerve fibers that innervate all aspects of this organ system. Appropriate innervation of the bladder and urethra are required for normal bladder contractility and urinary continence. Failure to regulate normal urine pressures within the bladder, as occurs in neurogenic bladder, predisposes to kidney failure when high pressures damage glomeruli. In children, Spina bifida (SB) and spinal dysraphism are the most common causes of neurogenic bladder dysfunction, with patients exhibiting deficits of bladder wall nerves and muscle. The association between neural tube defects and bladder dysfunction, as well as the NC origin of sympathetic and parasympathetic inputs that innervate the bladder, implies that NC derivatives are essential participants in normal bladder development. In vitro neural crest stem cells are capable of generating neurons, glia and myofibroblasts. However, a fate map of the LUT with cellular resolution that relates mature NC-derived cell types to structures within this organ system does not yet exist. Thus it remains to be seen whether only pelvic autonomic neurons and glia are NC-derived or if neural crest stem cells also contribute other essential cell types to the LUT. Alternatively, it is possible that NC-derived progenitors exert inductive effects on developing muscle in the LUT analogous to inductive mechanisms in cardiac and thymus development. We will test the hypothesis that multiple lineages within the bladder are NC- derived and are required for normal bladder development through analysis of engineered mouse models. Aim 1 will derive a comprehensive fate map of NC-derived lineages in the LUT. Aim 2 will define mechanisms of altered NC development in a mouse SB model that mimics LUT deficiencies seen in SB patients. Aim 3 will target temporal and tissue specific ablation of Pax3 to establish lineage requirements for this gene in directing NC progenitors as they populate the bladder. Our analysis will pioneer exploration of NC lineages in the bladder and identify altered developmental processes in a mouse model of SB that are relevant for understanding the etiology of bladder disease in SB patients.

我们的目标是揭示控制细胞类型形成的发展和遗传机制 从下尿路（LUT）中的神经rest（NC）。 NC祖细胞形成骨盆 沿神经纤维的自主神经节和周围神经胶质神经支配该器官的各个方面 系统。正常膀胱需要适当的膀胱和尿道支配 收缩和尿道。无法调节正常的尿液压力 正如神经源性膀胱中发生的膀胱 损坏肾小球。在儿童中，脊柱裂（SB）和脊柱异常是最常见的 神经源性膀胱功能障碍的原因，患者表现出膀胱壁神经的缺陷 和肌肉。神经管缺陷与膀胱功能障碍之间的关联以及 支配膀胱的交感神经和副交感神经输入的NC起源意味着 NC衍生物是正常膀胱发育中必不可少的参与者。体外神经rest 干细胞能够产生神经元，神经胶质和肌纤维细胞。但是，命运图 与细胞分辨率相关的LUT，将成熟的NC衍生的细胞类型与其中的结构相关联 器官系统尚不存在。因此，是否只有骨盆自主教是否只有 神经元和神经胶质是NC衍生的，或者神经rest干细胞也会贡献其他必需细胞 类型为LUT。另外，NC衍生的祖细胞可能发挥感应作用 在LUT中发展肌肉，类似于心脏和胸腺中的诱导机制 发展。我们将检验以下假设，即膀胱内的多个谱系是NC- 通过分析工程鼠标的分析，得出的正常膀胱发育需要并且是必需的 型号。 AIM 1将获得LUT中NC衍生血统的全面命运图。目标2 将定义模仿LUT的小鼠SB模型中NC开发改变的机制 SB患者出现缺陷。 AIM 3将靶向PAX3的时间和组织特异性消融 在指导NC祖细胞时建立该基因的谱系要求。 膀胱。我们的分析将开拓膀胱中NC谱系的探索并确定变化 SB的鼠标模型中的发展过程与理解 SB患者膀胱疾病的病因。