Functional Regeneration and Sprouting of Respiratory Pathways After Spinal Cord I

描述（由申请人提供）：C2半切导致同侧半膈麻痹。麻痹是由于延髓的球脊髓输入中断， 呼吸中枢到膈神经核然而，存在一个非常小的潜在通路，该通路下降到半切的对侧并穿过支配膈神经元的中线，基本上绕过了病变。正常的可塑性和这种所谓的“交叉膈通路”（CPP）的激活可以缓慢地恢复最初瘫痪的半侧膈肌的部分功能。电机 包括膈运动神经元在内的神经元被包裹在由硫酸软骨素蛋白聚糖（CSPG）构成的神经元周网中，硫酸软骨素蛋白聚糖是细胞外基质分子，其糖胺聚糖糖侧链产生不利于神经元发芽和突触可塑性的环境。形成瘢痕中的CSPG也阻断通过损伤部位的明显再生。最近的研究表明，软骨素酶ABC（ChABC）通过切割糖侧链具有消除神经束膜网和瘢痕相关基质的轴突生长抑制的能力，导致脊髓损伤后的再生和/或发芽。我们将测试的假设，通过酶促修饰抑制性细胞外基质周围膈运动神经元同侧的高颈半脊髓切断术，这种剩余的纤维从对侧的发芽能力，特别是那些的神经元能系统，将被最大化。在另外的实验中，我们将尝试使用间歇性缺氧或cAMP的药理学操作来驱动发芽纤维中的活性。最后，我们将构建一个跨越病变的PNS桥，以促进长距离再生，但也允许再生的轴突通过PNS/CNS界面处的抑制性ECM的降解离开桥。这种多方策略有可能导致SCI后前所未有的功能性呼吸可塑性/再生和恢复。公共卫生相关性：超过50%的脊髓损伤（SCI）发生在颈椎节段。SCI后的呼吸系统并发症是SCI人群绝望和死亡的主要原因。在这个建议中，我们计划利用C2脊髓半切模型SCI在成年啮齿动物研究潜在的疗法，以调节抑制性细胞外基质分子，试图促进再生和可塑性受损的呼吸通路。我们的策略有可能恢复在高颈椎水平受损的动物的呼吸。

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.