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

反射亢进是皮质脊髓束 (CST) 损伤的一种破坏性后果，无论是孤立的还是 其起源于皮质，或脊髓损伤（SCI）后。反射亢进背后有多种可能的机制。一 机制反映了 CST 丧失后损伤尾部本体感觉传入 (PA) 纤维的异常萌芽；和 更多的 PA 纤维在运动神经元上突触，PA 反射的强度可能会增强。 PA 端子通常是 在 GABA 能突触前抑制调节下。我们假设损伤后 PA 萌芽的发生无需 相关的 GABAergic 突触前调节，这可以增强反射动作，从而导致临床 反射亢进的后果，即痉挛和痉挛。 家长 R01 的总体重点是确定挫伤 SCI 后哪些运动障碍可能是由 归因于 CST 丢失，然后启动 CST 修复以针对特定损伤。拟议的 本多样性增刊中的研究将检验单侧锥体束中的 GABA 能失调假说 病变 (PTX)，一种模型损伤，可切断一个半球的所有 CST 轴突，而不会对脊髓造成损伤， 或颈脊髓挫伤，一种损害 CST 以及其他通路的临床前损伤模型， 脊髓的组成部分。我们将使用高分辨率形态学分析脊髓中 PA 突触的变化 灰质（目标 1）与新型多通道脊髓电生理记录方法（目标 2）相结合 解决反射亢进。 该项目第一年大部分时间的重点将是选择性 CST 病变 (PTX) 后的反射亢进。使用这个 Thelma 补充项目的 CST 病变模型通过提供额外的新颖性来补充母版 R01 SCI 重点 反射亢进问题的机制基础以及神经调节如何改善它。附近的 项目第一年完成后，候选人计划提交 NRSA F31 申请。顺利完成 拟议的第一年研究将使候选人能够根据强大的能力准备有竞争力的 NRSA F31 申请 有影响力的发现的前提。预计提交申请后将审查SCI损伤模型， 第二年。该项目的成功完成将为反射亢进的机制提供信息。 除了进行研究之外，候选人还将学习新的尖端技术，这些技术提供了新颖的方法 对反射亢进问题的独特视角，这将加强她与生理过程相关的训练 创伤后神经元兴奋性的潜在变化。 1