Neuroimmune Processes and Neuroplasticity in Chronic Spinal Cord Injury

慢性脊髓损伤的神经免疫过程和神经可塑性

• 批准号: 7862041
• 负责人: Harold David Shine
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7862041
• 关键词: Acute; Address; Axon; Belief; Biology; Biomedical Technology; Blocking Antibodies; Candidate Disease Gene; Chronic; Contralateral; Corticospinal Tracts; Distal; Environment; Gene Delivery; Gene Expression; Gene Proteins; Goals; Growth Factor; Immune; Immune Cell Activation; Immune response; Immune system; Immunoassay; Injury; Ipsilateral; Knowledge; Lead; Lesion; Leukocytes; Lipopolysaccharides; Measures; Mediating; Microglia; Modeling; Molecular; Motor Neurons; Natural regeneration; Nerve Degeneration; Neuroimmunomodulation; Neuronal Plasticity; Neurotrophin 3; Nude Rats; Patients; Phase; Play; Process; Rattus; Recovery; Role; Site; Source; Spinal Cord; Spinal Cord Lesions; Spinal cord injury; Spinal cord injury patients; T-Lymphocyte; Testing; Time; Tissue-Specific Gene Expression; Wallerian Degeneration; War; Work; Wound Healing; arm; axon growth; axon regeneration; axonal sprouting; base; central nervous system injury; chemokine; clinically significant; cytokine; immunosuppressed; injured; nerve injury; neurotrophic factor; peace; prevent; protein expression; reconstitution; release factor; repaired; research study; response

DESCRIPTION (provided by applicant): Over-expression of Neurotrophin-3 (NT-3) in lumbar motoneurons induces axons to grow from the contralateral corticospinal tract (CST) towards the source of NT-3 in rats but only if the CST ipsilateral to the transduced motoneurons is lesioned and if the NT-3 over-expression is coincident with the time of lesion. If NT-3 over-expression is delayed 4m after the lesion there is no axonal growth suggesting that at least one factor associated with the acute phase of the CST injury is involved. If the rats with acute CST lesions were immunosuppressed axonal growth in response to NT-3 is blocked. When the experiment was repeated in athymic nude (AN) rats there was no axonal growth in response to NT-3. If the immune response is re-activated in chronically lesioned rats with systemic lipopolysaccharide (LPS) NT-3 will induce axonal growth. This is the first demonstration of inducing axonal growth with neurotrophins in achronically lesioned CNS. These observations suggest that NT-3-induced axonal growth requires processes associated with immune-mediated wound healing; specifically activated T- cells. The goals of this project are to identify the factor or factors associated with immune-mediated wound healing and test them in conjunction with NT-3 in our model of chronic spinal cord injury. The specific aims are to: (1) verify the role of T-cells in NT-3-induced axonal growth, identify the T-cell subtype responsible, (2) determine the role of microglial activation in this process, and (3) identify genes and proteins differentially expressed in conditions that support NT-3 induced axonal growth compared to those that do not using qPCR and protein expression using multiplex array immunoassays in AN rats. Our results show that neuroplasticity can be induced in the chronically injured spinal cord distal to the lesion site. This neuroplasticity is likely induced by the presence of NT-3 and a factor, or factors, associated with immune-mediated wound healing. If the identity of the factor(s) associated with the acute injury can be identified then it may be possible to recapitulate the acute environment in patients with chronic spinal cord injuries to induce neuroplasticity in spared axonal tracts. Two-thirds of spinal cord injury patients have incomplete cord transections so strategies to enhance the function of the remaining connections by enabling the inherent plasticity of the CNS may provide improvement in function of patients with chronic spinal cord injury. PUBLIC HEALTH RELEVANCE: The Armed Forces' activities in both peace- and war-time present situations for catastrophic neural injuries. It is improbable with today's biomedical technologies that the injured CNS can be repaired by inducing the regeneration of severed axons. However, it is not improbable that some function may be gained by the CNS's innate ability to mount a compensatory reorganization through collateral sprouting of spared axons. This proposal is based upon our recent discoveries that immune-related processes are involved in axonal growth after injuryand that reactivating these immune processes will enable axonal growth in the chronic injured CNS. This work addresses the basic biology of recovery from SCI with the belief that this knowledge may be used to develop new, or refine existing, strategies to help repair these neural injuries. It seeks to determine the underlying mechanism of neurotrophin-induced axonal regeneration after SCI in order to develop means to treat chronic CNS injuries.

描述（由申请人提供）： 腰椎运动神经元中神经营养蛋白-3 (NT-3) 的过度表达会诱导轴突从对侧皮质脊髓束 (CST) 向大鼠的 NT-3 源生长，但前提是与转导运动神经元同侧的 CST 受损，并且如果NT-3过度表达与病变时间一致。如果 NT-3 过表达延迟到病变后 4m，则没有轴突生长，表明至少涉及一种与 CST 损伤急性期相关的因素。如果患有急性 CST 损伤的大鼠受到免疫抑制，则对 NT-3 的反应的轴突生长就会被阻断。当在无胸腺裸鼠（AN）中重复该实验时，没有出现响应 NT-3 的轴突生长。如果慢性损伤大鼠体内的免疫反应在全身性脂多糖 (LPS) 的作用下重新激活，NT-3 将诱导轴突生长。这是首次证明在慢性损伤的中枢神经系统中用神经营养素诱导轴突生长。这些观察结果表明 NT-3 诱导的轴突生长需要与免疫介导的伤口愈合相关的过程；特异性激活的 T 细胞。该项目的目标是确定与免疫介导的伤口愈合相关的一个或多个因素，并在我们的慢性脊髓损伤模型中结合 NT-3 对其进行测试。具体目标是：(1) 验证 T 细胞在 NT-3 诱导的轴突生长中的作用，确定负责的 T 细胞亚型，(2) 确定小胶质细胞激活在此过程中的作用，以及 (3)与不使用 qPCR 的条件相比，在支持 NT-3 诱导的轴突生长的条件下鉴定差异表达的基因和蛋白质，并使用多重阵列免疫测定法在 AN 大鼠中鉴定蛋白质表达。我们的结果表明，可以在病变部位远端的慢性损伤脊髓中诱导神经可塑性。这种神经可塑性可能是由 NT-3 和与免疫介导的伤口愈合相关的一个或多个因素的存在引起的。如果能够确定与急性损伤相关的因素，那么就有可能重现慢性脊髓损伤患者的急性环境，以诱导幸存的轴突束的神经可塑性。三分之二的脊髓损伤患者有不完全的脊髓横断，因此通过启用中枢神经系统固有的可塑性来增强剩余连接的功能的策略可能会改善慢性脊髓损伤患者的功能。 公共卫生相关性： 武装部队在和平时期和战时的活动都会造成灾难性的神经损伤。以当今的生物医学技术来说，通过诱导切断的轴突再生来修复受伤的中枢神经系统是不可能的。然而，中枢神经系统通过备用轴突的附带萌芽进行补偿性重组的先天能力可能会获得某些功能，这并非不可能。该提议基于我们最近的发现，即损伤后轴突生长涉及免疫相关过程，并且重新激活这些免疫过程将使慢性损伤的中枢神经系统中的轴突生长得以实现。这项工作涉及 SCI 恢复的基本生物学，相信这些知识可用于开发新的或完善现有的策略来帮助修复这些神经损伤。它试图确定 SCI 后神经营养蛋白诱导轴突再生的潜在机制，以便开发治疗慢性中枢神经系统损伤的方法。