Proteases in Spinal Cord Plasticity & Regeneration

脊髓可塑性中的蛋白酶

• 批准号: 6506070
• 负责人: NICHOLAS W SEEDS
• 金额: $ 30.45万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6506070
• 关键词: NMDA receptors; axon; genetically modified animals; immunocytochemistry; immunoelectron microscopy; in situ hybridization; laboratory mouse; laboratory rat; lung; messenger RNA; motor neurons; nervous system regeneration; neural plasticity; peripheral nervous system; phrenic nerve; plasminogen activator; plasminogen activator inhibitors; polymerase chain reaction; respiratory function; sensorimotor system; spinal cord injury; spinal ganglion; synaptic vesicles

DESCRIPTION (provided by applicant): Studies will focus on the potential role of extracellular proteases, namely the plasminogen activator/plasminogen (PA/pign) system in synaptic remodeling and axonal regeneration in the injured spinal cord of rodents. The PA/plgn system has been suggested to play a role both in axonal outgrowth and synaptic plasticity. The PA genes are induced following peripheral nerve injury and are required for timely PNS regeneration. Studies will be directed at assessing the role of these PA/plgn genes in the ability of dorsal root ganglia sensory axons to regenerate their CNS collaterals in the dorsal column of the spinal cord. Most importantly studies will be performed to assess whether the interesting crossed phrenic nerve response, an example of synaptic remodeling following spinal cord injury, requires the induction of the PA/pign system to promote these synaptic changes that permit a restoration of lung function. Mice deficient in various PA/plgn genes will be compared for their plasticity and regenerative abilities to demonstrate any requirement for these protease activities. Furthermore, expression of the PA/pign system [tissue plasminogen activator (tPA), urokinase plasminogen activator(uPA), plasminogen, plasminogen activator inhibitor-i (PAIl), and protease nexin(PN)] in the lesioned or injured spinal cord will be studied by in situ hybridization with 35S-CRNA probes and antibodies to these PA system proteins, to determine whether this gene system is also induced in the CNS and whether it plays a role in axonal regeneration and synaptic plasticity. An understanding of this protease system in the injured spinal cord may allow us to effectively enhance axonal regeneration by supplying either PA/plgn or their inhibitors to the site of injury. Similarly, PA/pign expression may be important for synaptic remodeling at sites below a spinal cord lesion, such that induction of the PA/pign genes may lead to partial restoration of function.

描述（由申请人提供）：研究将侧重于细胞外蛋白酶的潜在作用，即突触重塑和轴突再生在啮齿动物受伤的脊髓中的突触重塑和轴突再生中的纤溶酶原激活剂/纤溶酶原（PA/PIGN）系统。已建议PA/PLGN系统在轴突产物和突触可塑性中发挥作用。在周围神经损伤后诱导PA基因，是及时的PNS再生所必需的。研究将致力于评估这些PA/PLNG基因在背根神经节感觉轴突在脊髓背侧柱中再生中枢神经系统侧支的能力。最重要的是，将进行研究以评估有趣的跨性神经反应（脊髓损伤后突触重塑的一个例子）是否需要诱导PA/PIGN系统来促进这些突触变化，以允许恢复肺功能。将比较缺乏各种PA/PLGN基因的小鼠的可塑性和再生能力，以证明对这些蛋白酶活性的任何要求。此外，PA/PIGN系统的表达[组织纤溶酶原活化剂（TPA），尿激酶原生原激活剂（UPA），纤溶酶原，纤溶酶原，纤溶酶原激活剂抑制剂I（PAIL）（PAIL）和蛋白酶蛋白酶Nexin Nexin（PN）和脊髓中的脊髓中的探针将在355中进行研究。蛋白质，确定该基因系统是否也在中枢神经系统中诱导，以及它是否在轴突再生和突触可塑性中起作用。对受伤的脊髓中这种蛋白酶系统的理解可能使我们能够通过向损伤部位提供PA/PLGN或其抑制剂来有效增强轴突再生。同样，PA/PIGN表达对于在脊髓病变以下的部位进行突触重塑可能很重要，因此PA/PIGN基因的诱导可能导致功能的部分恢复。