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.

摘要 背根(DR)内有初级感觉神经元(DRG)的传入轴突，这些感觉神经元在DRG内传递 感觉信息传给脊髓中的二级神经元。DRS的创伤性损伤包括上臂 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，由高能量牵引损伤颈部DRS所致。这些损伤通常会引起慢性损伤。 令人痛苦、疼痛和永久失去知觉。我们没有有效的治疗方法可以减少 最初的损伤，或在后来的阶段，恢复感觉连接。因此，非常重要的是 全面了解创伤性损伤对DRS，特别是颈部DRS造成的损害程度，以及 损害发生的机制。DR损伤直接损害初级感觉神经轴突，导致 通过永久消除脊髓中的初级传入轴突而导致的感觉丧失。然而，人们普遍认为， 脊髓中的二级神经元保持完好。与这种信念相矛盾的是，我们偶然地 在小鼠身上发现，颈椎DR挤压可以引起脊髓严重的神经组织丢失，远远超过 比之前想象的要严重。值得注意的是，神经组织损伤的发生率和程度差异很大。 在小鼠中，有趣的是，在雄性和异种小鼠中，以及在撕脱DRS之后，临床上相关的 糖尿病视网膜损伤模型。我们假设DR损伤可以通过引发强烈的 脊髓缺血，当它损害动脉组织脆弱的小鼠的大神经根动脉时。 目标1将通过测试光血栓闭塞是否确实是脊髓损伤来确定脊髓损伤是否确实是缺血性的 完整的DRS中的大神经根动脉足以导致严重的脊髓神经组织丢失。目标2将 确定小鼠之间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，从而严重影响糖尿病视网膜病变的病理生理进展。当前 据了解，人类的脊髓缺血是由脊髓的直接损伤引起的，而不是由 远端伤及脊神经或周围神经。人类脊髓的血液供应也很高。 变量。因此，阐明这种新形式的脊髓缺血和并发脊髓损伤， 在小鼠身上，最终可能在诊断、治疗和预后方面提供新的方向 外科DR损伤。