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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

基本信息

批准号：
8097968
负责人：
Jerry Silver
金额：
$ 33.66万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8097968
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 Health 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 Time Tracer Up-Regulation axon growth axonal sprouting dextran dorsal column functional restoration immunoreactivity improved inhibitor/antagonist nerve supply raphe nuclei research study respiratory restoration serotonin transporter somatosensory sugar

项目摘要

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 半切导致同侧膈肌瘫痪。瘫痪是由于髓质的球脊髓输入中断造成的。呼吸中枢至膈核。然而，存在一条非常小的潜在通路，该通路从半切的对侧下降并穿过中线支配膈神经元，基本上绕过病变。这种所谓的“交叉膈通路”（CPP）的正常可塑性和激活可以缓慢恢复最初瘫痪的膈肌的部分功能。发动机神经元，包括膈运动神经元，被包裹在由硫酸软骨素蛋白聚糖（CSPG）组成的神经周网络中，这是一种细胞外基质分子，其糖胺聚糖侧链为神经元萌芽和突触可塑性创造了不利的环境。形成疤痕中的 CSPG 也会阻止损伤部位的明显再生。最近的研究表明，软骨素酶 ABC (ChABC) 通过裂解糖侧链能够消除神经周围网和疤痕相关基质的轴突生长抑制，从而在脊髓损伤后导致再生和/或发芽。我们将检验以下假设：通过酶促修饰高位颈半皮质切除术同侧膈运动神经元周围神经元周围网络中的抑制性细胞外基质，对侧剩余纤维的萌芽能力，尤其是血清素能系统的萌芽能力将最大化。在其他实验中，我们将尝试使用间歇性缺氧或 cAMP 的药理操作来驱动发芽纤维的活性。最后，我们将在病变处构建一个 PNS 桥，以促进长距离再生，但也允许再生的轴突通过 PNS/CNS 界面处抑制性 ECM 的降解而离开桥。这种多方策略有可能在 SCI 后带来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) 发生在颈部。 SCI 后的呼吸系统并发症是 SCI 人群绝望和死亡的主要原因之一。在本提案中，我们计划利用成年啮齿类动物 SCI 的 C2 脊髓半切模型来研究调节抑制性细胞外基质分子的潜在疗法，以试图促进受损呼吸通路的再生和可塑性。我们的策略有可能恢复高颈椎病变动物的呼吸。