Diversity Supplement to 2R01NS064004

2R01NS064004 的多样性补充

• 批准号: 10303610
• 负责人: John H Martin
• 金额: $ 3.07万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303610
• 关键词: 3-Dimensional; Address; Affect; Axon; Biological Assay; Cells; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Clinical; Complement; Conditioned Reflex; Confocal Microscopy; Corticospinal Tracts; Dendrites; Development; Electrodes; Electrophysiology (science); Fiber; Funding; Hand functions; Horns; Hyperreflexia; Impairment; Injury; Label; Learning; Lesion; Modeling; Morphology; Motor; Motor Neurons; Muscle; National Research Service Awards; Outcome; Outcome Measure; Parents; Pathway interactions; Physiological Processes; Positioning Attribute; Presynaptic Terminals; Pyramidal Tracts; Reflex action; Regulation; Research; Resolution; Sensory; Side; Silicon; Spasm; Spinal; Spinal Cord; Spinal Cord Contusions; Spinal Injuries; Spinal cord injury; Synapses; System; Techniques; Training; Trauma; Traumatic CNS injury; Upper Extremity; base; extracellular; gray matter; indexing; injured; motor impairment; neuronal cell body; neuronal excitability; neuroregulation; novel; pre-clinical; presynaptic; reconstruction; repaired; response; spasticity

Hyperreflexia is a devastating consequence of a lesion that damages the corticospinal tract (CST), in isolation, or at its origins in the cortex, or after a spinal cord injury (SCI). Multiple possible mechanisms underlie hyperreflexia. One mechanism reflects aberrant sprouting of proprioceptive afferent (PA) fibers caudal to the injury after CST loss; with more PA fibers synapsing on motoneurons, the strength of PA reflexes may be augmented. PA terminals are normally under GABAergic presynaptic inhibitory regulation. We hypothesize that PA sprouting after an injury occurs without associated GABAergic presynaptic regulation and that this can enhance reflex actions, leading to the clinical consequences of hyperreflexia, which is spasticity and spasms. An overall focus of the parent R01 is to determine which motor impairments after a contusion SCI may be attributable to the loss of the CST, and then to initiate CST repair to target the particular impairment. The proposed studies in this Diversity Supplement will examine the GABAergic dysregulation hypothesis in a unilateral pyramidal tract lesion (PTX), a model injury that severs all CST axons from one hemisphere without producing injury to the spinal cord, or a cervical spinal cord contusion, a preclinical injury model that lesions the CST as well as other pathways and components of the spinal cord. We will use high-resolution morphologic analyses of PA synapse changes in the spinal gray matter (Aim 1) together with a novel multi-channel spinal cord electrophysiological recording approach (Aim 2) to address hyperreflexia. The focus for most of year 1 of the project will be on hyperreflexia after selective CST lesion (PTX). Using this CST lesion model for Thelma's supplement project complements the parent R01 SCI focus by providing additional novel mechanistic underpinnings of the problem of hyperreflexia and how neuromodulation can ameliorate it. Near the completion of year 1 of the project, the candidate plans to submit an NRSA F31 application. Successful completion of proposed year 1 studies will position the candidate to prepare a competitive NRSA F31 application based on a strong premise of impactful findings. It is expected that the SCI injury model will be examined after application submission, during year 2. Successful completion of the project will inform the mechanisms of hyperreflexia. In addition to conducting the research, the candidate will learn new cutting-edge techniques that provide a novel and unique perspective on the problem of hyperreflexia and this will bolster her training related to physiological processes underlying changes in neuronal excitability after trauma. 1

超反射症是造成皮质脊髓束（CST）的病变的毁灭性结果，孤立或 起源于皮质，或脊髓损伤后（SCI）。多种可能的机制是高反射症的基础。一 机制反映了本体感受传入（PA）纤维的异常发芽，尾部是CST损失后的损伤。和 在运动神经元上突触的更多PA纤维，PA反射的强度可能会增加。 PA终端通常为 在GABA能突触前抑制性调节下。我们假设PA在受伤后发芽没有 相关的GABA能突触前调节，这可以增强反射作用，导致临床 超反射症的后果，即痉挛和痉挛。 母体R01的总体重点是确定挫伤SCI后哪些运动障碍 归因于CST的损失，然后启动CST修复以针对特定损伤。提议 对这种多样性补充的研究将检查单方面锥体的GABA能失调假设 病变（PTX），一种模型损伤，可将所有CST轴突从一个半球切断而不导致脊髓损伤， 或宫颈脊髓挫伤，这是一种临床前损伤模型，该模型在CST以及其他途径和其他途径中都有 脊髓的成分。我们将使用脊柱中PA突触变化的高分辨率形态分析 灰质（AIM 1）以及一种新型的多渠道脊髓电生理记录方法（AIM 2） 解决高反射症。 在选择性CST病变（PTX）之后，该项目大部分时间的重点将放在超反射症上。使用此 Thelma补充项目的CST病变模型通过提供其他小说来补充父母R01 SCI的重点 高反复症问题的机械基础以及神经调节如何改善它。附近 该项目的第一年完成，候选人计划提交NRSA F31申请。成功完成 拟议的第一年研究将使候选人定位，以基于强大 有影响力的发现的前提。预计将在提交申请后检查SCI伤害模型， 在第二年。成功完成该项目将为超反射症的机制提供信息。 除了进行研究外，候选人还将学习新的尖端技术，以提供新颖的技术 以及关于超反射性问题的独特观点，这将加强她与生理过程有关的培训 创伤后神经元兴奋性的基本变化。 1