Functional Regeneration and Sprouting of Respiratory Pathways After Spinal Cord I

描述(申请人提供)：C2半切导致同侧横隔膜瘫痪。麻痹是延髓的球脊髓输入中断的结果。 呼吸中枢至膈神经核。然而，存在一条非常小的潜在路径，它从对侧下行，穿过支配膈神经的中线，基本上绕过了病变。这种所谓的“交叉膈神经通路”(CPP)的正常可塑性和激活可以缓慢地恢复最初瘫痪的半横肌的部分功能。马达 神经元，包括膈运动神经元，被包裹在由硫酸软骨素蛋白多糖(CSPGs)组成的神经周围网络中，CSPGs是细胞外基质分子，其糖胺多糖侧链为神经元的萌发和突触可塑性创造了不利的环境。瘢痕形成过程中的CSPG也会阻碍通过病变部位的显性再生。最近的研究表明，软骨素酶ABC(ChABC)通过裂解糖侧链，具有消除脊髓损伤后神经周围神经网络和瘢痕相关基质的轴突生长抑制，导致再生和/或发芽的能力。我们将测试这一假设，即通过对高位颈椎偏侧切断术同侧膈运动神经元周围的神经神经网中的抑制性细胞外基质进行酶修饰，来自对侧的这些剩余纤维的出芽能力将被最大化，特别是5-羟色胺能系统的出芽能力。在其他实验中，我们将尝试使用间歇性低氧或对cAMP的药理操作来促进发芽纤维的活性。最后，我们将构建一座跨越损伤的PNS桥，以促进远距离再生，同时也允许再生的轴突通过降解PNS/CNS界面上的抑制性ECM离开桥。这种多方策略有可能导致前所未有的功能呼吸可塑性/再生和脊髓损伤后的恢复。公共卫生相关性：超过50%的脊髓损伤(SCI)发生在颈椎水平。脊髓损伤后的呼吸道并发症是导致脊髓损伤人群绝望和死亡的一些主要原因。在这项建议中，我们计划利用成年啮齿动物脊髓损伤的C2脊髓半横断模型来研究潜在的治疗方法，以调节抑制性细胞外基质分子，试图促进受损呼吸道的再生和可塑性。我们的策略有可能恢复颈部高度受损的动物的呼吸。

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.