Dorsal root injury and ischemic spinal cord injury

背根损伤和缺血性脊髓损伤

• 批准号: 10317545
• 负责人: YOUNG-JIN SON
• 金额: $ 43.59万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317545
• 关键词: Adult; Afferent Neurons; Animals; Area; Arteries; Astrocytes; Attention; Axon; Belief; Brachial plexus structure; Cauda Equina; Cells; Cervical; Child; Chronic; Data; Diagnosis; Disease; Dorsal; Ganglia; Glial Fibrillary Acidic Protein; Horns; Human; Image; Inbreeding; Incidence; Individual; Infarction; Inflammatory; Injury; Investigation; Ischemia; Label; Lead; Lesion; Lumbosacral plexus structure; Modeling; Mus; Muscle Spasticity; Natural regeneration; Neurologic Deficit; Neurons; Neurosurgical Procedures; Numbness; Obstruction; Oligodendroglia; Operative Surgical Procedures; Pain; Patients; Pattern; Peripheral; Peripheral Nerves; Plant Roots; Prognosis; Reporting; Rhizotomy procedure; Sensory; Severities; Spinal; Spinal Artery; Spinal Cord; Spinal Cord Ischemia; Spinal Ganglia; Spinal cord damage; Spinal cord injury; Spinal nerve root structure; Spinal nerve structure; Stroke; Testing; Thrombosis; Tissues; Traction; Trauma; Traumatic injury; Vascular blood supply; afferent nerve; axon injury; axon regeneration; axonal degeneration; clinically relevant; dorsal horn; effective therapy; experimental study; gray matter; improved; insight; male; mouse model; nerve damage; nerve injury; novel; relating to nervous system; restoration; spinal nerve posterior root; vascular inflammation

Abstract The dorsal root (DR) carries afferent axons of primary sensory neurons in the DR ganglion (DRG), which relay sensory information to second order neurons in the spinal cord. Traumatic injuries to DRs include brachial plexus, lumbosacral plexus and cauda equina injuries. Brachial plexus injury (BPI), the most common form of DR injury, results from high-energy traction damaging cervical DRs. These injuries evoke chronic, often agonizing, pain and permanent loss of sensation. We have no effective therapies that can reduce the extent of the initial injury or, at a later stage, restore sensory connections. It is therefore extremely important to understand the full extent of the damage caused by traumatic injuries to DRs, especially cervical DRs, and the mechanisms by which the damage occurs. DR injury directly damages primary sensory axons, resulting in sensory loss by permanently eliminating primary afferent axons in spinal cord. It is widely believed, however, that second order neurons in spinal cord remain intact. In contradiction to this belief, we have serendipitously found in mice that cervical DR crush can provoke profound neural tissue loss in spinal cord that is far more severe than previously thought. Notably, the incidence and magnitude of the neural tissue damage vary widely among mice, and interestingly increase in males and outbred mice and after avulsing DRs, a clinically relevant model of DR injury. We hypothesize that DR injury can cause severe spinal cord damage by eliciting intense spinal cord ischemia, when it damages large radicular arteries in mice with vulnerable arterial organization. Aim 1 will determine if the spinal cord damage is indeed ischemic by testing if photothrombotic occlusion of large radicular arteries in intact DRs is sufficient to elicit severe neural tissue loss in spinal cord. Aim 2 will determine if wide variability of arterial organization among mice determines the incidence and severity of spinal cord ischemia, thus critically impacting the pathophysiological progression of DR injuries. Current understanding is that spinal cord ischemia in humans is caused by direct damage to spinal cord, but not by remote trauma to spinal roots or peripheral nerve. The blood supply of the spinal cord in humans is also highly variable. Therefore, elucidation of this novel form of spinal cord ischemia and concurrent spinal cord damage, in mice, may ultimately provide new directions in the diagnosis, treatment and prognosis of both sporadic and surgical DR injuries.

抽象的 背根 (DR) 携带 DR 神经节 (DRG) 中初级感觉神经元的传入轴突，负责中继 脊髓二阶神经元的感觉信息。 DR 的外伤包括肱骨 神经丛、腰骶丛和马尾神经损伤。臂丛神经损伤 (BPI)，最常见的形式 DR 损伤是由高能牵引损伤颈椎 DR 造成的。这些伤害通常会引起慢性 痛苦、痛苦和永久失去知觉。我们没有有效的疗法可以减少 最初的损伤，或者在后期恢复感觉连接。因此极其重要 了解外伤对 DR（尤其是颈椎 DR）造成的损害的全部程度，以及 损害发生的机制。 DR损伤直接损害初级感觉轴突，导致 通过永久消除脊髓中的初级传入轴突而导致感觉丧失。然而，人们普遍认为， 脊髓中的二级神经元保持完整。与这一信念相矛盾的是，我们偶然发现了 在小鼠中发现，颈椎 DR 挤压会引起脊髓中神经组织的严重损失，这种损失要严重得多 比之前想象的严重。值得注意的是，神经组织损伤的发生率和严重程度差异很大 在小鼠中，有趣的是，在雄性和远交小鼠中增加，并且在撕脱 DR 后，临床相关的 DR损伤模型。我们假设 DR 损伤可通过引发强烈的脊髓损伤而导致严重的脊髓损伤。 脊髓缺血，当它损害动脉组织脆弱的小鼠的大根动脉时。 目标 1 将通过测试脊髓是否发生光血栓闭塞来确定脊髓损伤是否确实是缺血性的。 完整的 DR 中的大根动脉足以引起脊髓中严重的神经组织损失。目标2将 确定小鼠动脉组织的广泛变异性是否决定了脊髓损伤的发生率和严重程度 脊髓缺血，从而严重影响 DR 损伤的病理生理进展。当前的 据了解，人类脊髓缺血是由脊髓直接损伤引起的，而不是由脊髓损伤引起的。 脊髓根或周围神经的远程创伤。人体脊髓的血液供应也非常丰富 多变的。因此，阐明这种新型脊髓缺血和并发脊髓损伤， 在小鼠中，可能最终为散发性和 手术 DR 损伤。