Functional Regeneration and Sprouting of Respiratory Pathways After Spinal Cord I

脊髓 I 后呼吸通路的功能再生和萌芽

• 批准号: 7874448
• 负责人: Jerry Silver
• 金额: $ 34万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874448
• 关键词: Acute; Address; Adult; Animals; Antibodies; Area; Attenuated; Autologous; Axon; Bilateral; Brain Stem; Breathing; Bypass; Cell Nucleus; Cervical; Cessation of life; Chondroitin ABC Lyase; Chondroitin Sulfate Proteoglycan; Cicatrix; Cleaved cell; Combined Modality Therapy; Contralateral; Cyclic AMP; Denervation; Dextrans; Environment; Enzymes; Extracellular Matrix; Family; Fiber; Glycosaminoglycans; Growth; Hypoxia; Immunohistochemistry; Injury; Ipsilateral; Label; Lead; Lectin; Left; Length; Lesion; Mediating; Methods; Modeling; Motor; Motor Neurons; Natural regeneration; Nerve Crush; Neurons; Paper; Paralysed; Pathway interactions; Peripheral Nerves; Pharmacological Treatment; Population; Process; Proteoglycan; Rattus; Recovery; Recovery of Function; Respiratory Center; Respiratory Diaphragm; Rodent; Serotonin; Serotonin Antagonists; Side; Silver; Site; Source; Spinal Cord; Spinal cord injury; Staining method; Stains; Structure of phrenic nerve; Synaptic plasticity; System; Testing; Texas red; Time; Tracer; Up-Regulation; axon growth; axonal sprouting; dextran; dorsal column; functional restoration; immunoreactivity; improved; inhibitor/antagonist; nerve supply; public health relevance; raphe nuclei; research study; respiratory; restoration; serotonin transporter; somatosensory; sugar

DESCRIPTION (provided by applicant): C2 hemisection results in paralysis of the ipsilateral hemidiaphragm. The paralysis is a result of disruption of bulbospinal inputs from medullary respiratory centers to the phrenic nucleus. However, there exists a very small, latent pathway that descends contralateral to the hemisection and crosses the midline innervating phrenic neurons, essentially bypassing the lesion. Normal plasticity and activation of this so-called "crossed phrenic pathway" (CPP) can slowly restore partial function to the initially paralyzed hemidiaphragm. Motor neurons, including phrenic motor neurons, are enveloped in a perineuronal net that is composed of chondroitin sulfate proteoglycans (CSPGs), extracellular matrix molecules whose glycosaminoglycan sugar side chains create an unfavorable environment for neuronal sprouting and synaptic plasticity. CSPGs in the forming scar also block overt regeneration through the lesion site. Recent studies have demonstrated that the enzyme chondroitinase ABC (ChABC) by cleaving the sugar side chains has the ability to abrogate axon growth inhibition of both the perineuronal net and scar-associated matrix resulting in regeneration and/or sprouting after spinal cord injury. We will test the hypothesis that, by enzymatically modifying inhibitory extracellular matrices in the perineuronal net surrounding phrenic motor neurons ipsilateral to a high cervical hemicordotomy, the sprouting capacity of such remaining fibers from the contralateral side, especially those of the serotonergic system, will be maximized. In additional experiments we will attempt to drive activity in the sprouted fibers using intermittent hypoxia or pharmacological manipulation of cAMP. Finally, we will construct a PNS bridge across the lesion to promote long distance regeneration but also allow regenerated axons to exit the bridge via degradation of inhibitory ECM at the PNS/CNS interface. This multipartite strategy has the potential to lead to an unprecedented amount of functional respiratory plasticity/regeneration and recovery after SCI. PUBLIC HEALTH RELEVANCE: Greater than 50% of all spinal cord injuries (SCI) occur at the cervical level. Respiratory complications following SCI are some of the leading causes of despair and death in the SCI population. In this proposal, we plan to utilize a C2 spinal cord hemisection model of SCI in adult rodents to investigate potential therapies to modulate inhibitory extracellular matrix molecules in an attempt to promote regeneration and plasticity of damaged respiratory pathways. Our strategy has the potential to restore breathing in animals lesioned at high cervical levels.

描述（由申请人提供）：C2半分裂导致同侧半脑瘫痪。瘫痪是髓质输入囊的结果 呼吸道中心于胎核。然而，存在非常小的潜在途径，与半分裂对侧并跨越了中线神经神经元，基本上绕过病变。这种所谓的“交叉途径”（CPP）的正常可塑性和激活可以慢慢恢复最初瘫痪的半脑肌的部分功能。发动机 神经元，包括Phrenic运动神经元，被包裹在由硫酸软骨蛋白蛋白聚糖（CSPGS）组成的会内神经元网中，细胞外基质分子的糖胺聚糖糖侧链为神经元萌芽和synaptic塑料带来了不利的环境。形成疤痕中的CSPG还通过病变部位阻止了明显的再生。最近的研究表明，通过切割糖侧链的酶软骨素酶ABC（CHABC）具有消除轴突生长抑制的能力，对脊髓损伤后的轴突脱神经元净和疤痕相关的基质均导致再生和/或发芽。我们将检验以下假设：通过酶促修饰围绕Phrenic运动神经元的抑制性细胞外矩阵，以相对于高宫颈半侧切开术的phrenic运动神经元同侧，而剩余的纤维的发芽能力，尤其是对对侧的纤维，尤其是血清素系统的那些。在其他实验中，我们将尝试使用间歇性缺氧或CAMP的药理学操纵来驱动发芽纤维的活动。最后，我们将在病变上构建一个PNS桥，以促进长距离再生，但也允许再生轴突通过在PNS/CNS界面处的抑制性ECM降解来退出桥梁。这种多部分策略有可能导致SCI后史无前例的功能性呼吸可塑性/再生和恢复。公共卫生相关性：大于所有脊髓损伤（SCI）的50％发生在宫颈水平。 SCI后的呼吸并发症是SCI人群绝望和死亡的一些主要原因。在此提案中，我们计划利用成年啮齿动物中SCI的C2脊髓半分裂模型来研究潜在的疗法，以调节抑制性细胞外基质分子，以促进受损呼吸道途径的再生和可塑性。我们的策略有可能恢复在高宫颈水平上病变的动物的呼吸。