Neuronal Somatic Response to Traumatic Brain Injury

对脑外伤的神经体反应

• 批准号: 6805238
• 负责人: John T Povlishock
• 金额: $ 34.69万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805238
• 关键词: brain injury; calcium flux; cell component structure /function; cell death; cell membrane; cell population study; cytoskeleton; denervation; electron microscopy; fluorescence microscopy; fluorescent dye /probe; immunocytochemistry; laboratory rat; light microscopy; membrane permeability; nervous system regeneration; neural degeneration; neurophysiology; soma; trauma

DESCRIPTION (provided by applicant): This amended application seeks to explore a relatively unchartered area in the pathobiology of traumatic brain injury (TBI) focusing on those injuries involving diffuse damage to the brain. Unlike the majority of contemporary TBI literature which focuses on focal change, most of which entails large destructive lesions such as contusion and hematoma formation, this application explores the potential that diffuse TBI, not complicated by focal lesions or secondary insult, evokes diffuse changes in either the neuronal somatic plasma membrane or perisomatic axonal appendages. Specifically, we posit that the forces of injury are capable of mechanically porating the intact plasma membrane causing either enduring or transient membrane perturbations that can respectively participate in progressive damage leading to cell death or membrane resealing and cell recovery. The same forces of injury are also envisioned to evoke, in other populations of neurons, perisomatic axotomy. It is posited that this TBI-induced damage translates into neuronal somatic perturbation. However, in contrast to published literature, we posit that most neurons do not die. Rather they undergo a reparative attempt. These premises will be explored in two well characterized models of TBI, fluid percussion and impact acceleration TBI. The potential for plasma membrane poration and resealing will be assessed via different molecular in weight/size tracers administered intrathecally at various time points pre and post injury. Companion quantitative studies using the principles of modern stereology will assess the numbers of neurons involved in this complex pathobiology within specific domains of the neocortex. Parallel LM immunocytochemical and ultrastructural analyses will provide for the direct assessment of membrane integrity and related cytoskeletal, organelle or nuclear changes that correlate either with cell recovery or a progression of damage leading to death. Intrathecal tracers will be used in those neurons sustaining perisomatic axotomy to exclude the potential for plasma membrane potation, while using parallel immunocytochemical approaches to understand if such axotomized neurons progress to cell death or rather undergo transient perturbation with reorganization and repair. Collectively, these studies should reshape our appreciation of the complex pathobiology of TBI.

描述（由申请人提供）：本修订后的申请旨在探索创伤性脑损伤（TBI）病理学中相对未知的领域，重点关注涉及大脑弥漫性损伤的损伤。与大多数当代 TBI 文献重点关注局灶性变化（其中大多数会导致大的破坏性病变，如挫伤和血肿形成）不同，本应用探索了弥漫性 TBI（不因局灶性病变或继发性损伤而复杂化）引起神经元体细胞质膜或周围轴突附属物弥漫性变化的潜力。具体来说，我们假设损伤力能够机械地穿孔完整的质膜，导致持久或短暂的膜扰动，这些扰动可以分别参与导致细胞死亡或膜重新密封和细胞恢复的进行性损伤。预计同样的损伤力也会在其他神经元群体中引起体周轴突切断术。据推测，这种 TBI 引起的损伤会转化为神经元躯体扰动。然而，与已发表的文献相反，我们假设大多数神经元不会死亡。相反，他们会进行修复尝试。这些前提将在两个特征明确的 TBI 模型（流体冲击和冲击加速 TBI）中进行探索。将通过在损伤前后的不同时间点鞘内施用不同分子重量/大小的示踪剂来评估质膜穿孔和重新密封的潜力。使用现代体视学原理的定量研究将评估新皮质特定区域内参与这种复杂病理学的神经元数量。并行LM免疫细胞化学和超微结构分析将提供对膜完整性和相关细胞骨架、细胞器或核变化的直接评估，这些变化与细胞恢复或导致死亡的损伤进展相关。鞘内示踪剂将用于那些维持轴突周围切断的神经元，以排除质膜电位的可能性，同时使用平行免疫细胞化学方法来了解这些轴突切断的神经元是否进展到细胞死亡，或者更确切地说经历重组和修复的短暂扰动。总的来说，这些研究应该重塑我们对 TBI 复杂病理学的认识。