Targeting Spinal Dopaminergic Machinery to Improve Urinary Function after Spinal Cord Injury

针对脊髓多巴胺能机制改善脊髓损伤后的排尿功能

• 批准号: 9906406
• 负责人: Jaclyn H DeFinis
• 金额: $ 4.5万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-05 至 2022-09-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906406
• 关键词: Adult; Affect; Ataxia; Biological Assay; Bladder; Carboxy-Lyases; Catheterization; Cell Separation; Cells; Chest; Data; Development; Dopamine; Electromyography; Fiber; Fluorescence-Activated Cell Sorting; Functional disorder; Gene Expression; Genetic; Health; Histologic; Home environment; Hyperreflexia; Immunohistochemistry; Incontinence; Injury; Intervention; Kidney Failure; Label; Lead; Levodopa; Life; Location; Lower urinary tract; Maps; Measures; Medical; Metabolic; Micturition Reflex; Molecular; Morbidity - disease rate; Neonatal; Neurons; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Quality of life; Rabies virus; Rattus; Recovery; Recurrence; Reflex action; Regulation; Reporting; Residual state; Risk; Role; Signal Transduction; Social Work; Source; Sphincter; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Spinal cord injury patients; Symptoms; System; Techniques; Testing; Time; Tracer; Transgenic Organisms; Tyrosine; Tyrosine 3-Monooxygenase; United States Food and Drug Administration; Urethral sphincter; Urinary tract infection; Urination; Urine; Urodynamics; Variant; cohort; designer receptors exclusively activated by designer drugs; effective therapy; experimental study; genetic analysis; hospital readmission; improved; mortality; neonate; neuronal circuitry; new therapeutic target; postnatal; red fluorescent protein; response to injury; spinal reflex; transcription factor; urinary

PROJECT SUMMARY/ABSTRACT Traumatic spinal cord injury (SCI) often results in lower urinary tract dysfunction. Although a spinal bladder reflex can be established over time, loss of supraspinal modulation causes detrusor-sphincter dyssynergia and bladder hyperreflexia, which manifests as incontinence and inefficient voiding. The aforementioned symptoms eventually lead to urinary tract infections and, in some cases, kidney failure. Currently, urinary complications are one of the leading causes of morbidity and mortality in SCI patients. While spontaneous reorganization of spinal neuronal circuits occurs after injury, the extent is limited and the underlying mechanisms are not well understood. Recently, we discovered that a subpopulation of tyrosine hydroxylase (TH+) cells reside within the lower spinal cord that sustain dopamine (DA) levels and regulate the recovered bladder reflex after SCI. This is similar to what was observed in neonates. Accordingly, we hypothesize that, following SCI, spinal DA-related neurons reemerge as a primitive residual response to injury that regulates the micturition reflex, and increasing spinal DA signaling improves functional urinary recovery. In Aim 1, we will employ histological, fluorescent cell sorting and genetic analyses to determine if spinal DA-related cells of neonate and adult SCI rats share a similar distribution and molecular features. Transsynaptic tracing will illuminate if these cells are involved in the spinal micturition reflex circuitry. In Aim 2, using chemogenetic techniques and micturition reflex assessments, we will elucidate whether spinal TH+ cells regulate the recovered micturition reflex following SCI, and if enhancing spinal DA signaling improves urinary function. Overall, the results will help to better understand the role of the spinal dopaminergic system in the recovered bladder reflex and examine the efficacy of a novel therapeutic target for micturition dysfunction after SCI.

项目总结/摘要 创伤性脊髓损伤（SCI）常导致下尿路功能障碍。虽然脊柱 随着时间的推移，膀胱反射可以建立起来，失去脊髓上的调制， 协同失调和膀胱反射亢进，表现为失禁和无效排尿。的 上述症状最终导致尿路感染，在某些情况下，导致肾衰竭。 目前，泌尿系统并发症是SCI患者发病和死亡的主要原因之一。而 脊髓神经元回路的自发重组发生在损伤后，程度有限，潜在的 机制还不太清楚。最近，我们发现酪氨酸羟化酶亚群 (TH+）细胞驻留在较低的脊髓内，维持多巴胺（DA）水平并调节恢复的多巴胺（DA）水平。 脊髓损伤后膀胱反射这与在新生儿中观察到的情况相似。因此，我们假设， 脊髓损伤后，脊髓DA相关神经元作为对损伤的原始残留反应重新出现， 排尿反射和增加脊髓DA信号传导改善功能性排尿恢复。在目标1中，我们 采用组织学、荧光细胞分选和遗传分析，以确定是否存在脊髓DA相关细胞， 新生和成年SCI大鼠具有相似的分布和分子特征。跨突触追踪将 阐明这些细胞是否参与脊髓排尿反射回路。在目标2中，使用化学遗传学 技术和排尿反射评估，我们将阐明是否脊髓TH+细胞调节恢复 脊髓损伤后的排尿反射，以及增强脊髓DA信号是否改善排尿功能。总体看 结果将有助于更好地了解脊髓多巴胺能系统在恢复膀胱反射中的作用 并检测一种新的治疗靶点对SCI后排尿功能障碍的疗效。