CSPG receptors and PTEN in CNS regeneration

CSPG 受体和 PTEN 在 CNS 再生中的作用

• 批准号: 8696112
• 负责人: SHUXIN LI
• 金额: $ 34.07万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696112
• 关键词: Address; Adult; Area; Axon; Behavioral; Chondroitin Sulfate Proteoglycan; Cicatrix; Development; Dose; Environment; Failure; Fiber; Growth; In Vitro; Injury; Intrinsic factor; Knock-out; Knockout Mice; Lesion; Locomotor Recovery; Mediating; Modeling; Molecular; Molecular Target; Mus; Natural regeneration; Neurites; Neurons; Optic Nerve; PTEN gene; Pathway interactions; Patients; Peptides; Phosphoric Monoester Hydrolases; Recovery; Recovery of Function; Rodent; Signal Pathway; Signal Transduction; Site; Spinal Cord transection injury; Spinal cord injury; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Genes; axon growth; axon regeneration; base; central nervous system injury; combinatorial; design; extracellular; improved; in vivo; inhibitor/antagonist; inhibitory neuron; injured; mimetics; novel; novel strategies; public health relevance; receptor; regenerative; research study

DESCRIPTION (provided by applicant): By using novel, systemically deliverable, small inhibitory peptides developed in the PI's lab, we aim to determine whether targeting both extracellular inhibitory and neuron-intrinsic factors can markedly improve axon regeneration and functional recovery after spinal cord injury (SCI). Severed CNS axons fail to regenerate due to the extrinsic inhibitory environment and the reduced intrinsic growth capacity of mature neurons. Chondroitin sulfate proteoglycans (CSPGs) generated by glial scars strongly suppress axon extension into and beyond the lesion area and are the major molecular targets for treating SCI. Recently, we and other labs identified the LAR and PTP¿ phosphatases as receptors that mediate CSPG inhibition. Deleting either of them stimulated axon growth after SCI. Recent studies using conditional knockout mice suggested that PTEN critically restricts the intrinsic regenerative capacity of injured CNS axons. Thus, suppressing CSPG receptors and PTEN is promising for promoting axon regeneration after CNS injury. We have designed small peptides to block functions of these inhibitory molecules by targeting their specific domains and demonstrated the high efficacy of our peptides for promoting axon growth in vitro and in vivo. Since CSPGs and PTEN appear to limit growth by different signaling pathways, inhibition of both may act synergistically to promote axon regeneration by reducing environmental inhibitory influence at the lesion site and enhancing intrinsic growth capacity of mature neurons. We hypothesize that CSPGs and PTEN are critical contributors to regenerative failure of CNS neurons and that combined inhibition of both promotes axon regeneration better than inhibition of either one alone. We propose to address the following 3 Specific Aims: 1) determine whether transgenic deletion or peptide blockade of two CSPG receptors yields better axon growth in vitro and in vivo and functional recovery in adult mice with SCI than suppressing either receptor alone; 2) determine whether PTEN blockade with peptides stimulates similar degrees of axon growth and functional recovery as transgenic PTEN deletion in vitro and in vivo; 3) determine whether blocking both CSPG signaling and PTEN with peptides promotes greater axon regeneration and behavioral recovery after SCI than blocking either one alone. The results of peptide treatments will be compared with those of transgenic mouse experiments. Our novel strategy to administer small compounds systemically alone or in combination may facilitate development of a practical therapy for CNS injury.

描述（由适用提供）：通过使用PI实验室中开发的新型，全身可传递的小抑制性肽，我们旨在确定是否靶向细胞外抑制性和神经性因子是否可以显着改善轴突再生和脊髓损伤后的功能恢复（SCI）。由于外部抑制环境和成熟神经元的内在生长能力降低，切断的中枢神经系统轴突无法再生。神经胶质疤痕产生的硫酸软骨蛋白聚糖（CSPGS）强烈抑制轴突在病变区域内外延伸，并且是治疗SCI的主要分子靶标。最近，我们和其他实验室将LAR和PTP磷酸酶确定为介导CSPG抑制作用的受体。删除它们中的任何一个都刺激了SCI后的轴突生长。最近使用条件敲除小鼠的研究表明，PTEN严重限制了受伤的中枢神经系统轴突的内在再生能力。那抑制CSPG受体和PTEN有望在CNS损伤后促进轴突再生。我们已经设计了小肽来通过靶向其特定域来阻断这些抑制分子的功能，并证明了我们的Petides在体外和体内促进轴突生长的高效率。由于CSPG和PTEN似乎通过不同的信号通路限制了生长，因此两者的抑制可能会协同作用，以促进轴突再生，通过减少病变部位的环境抑制作用并增强成熟神经元的内在生长能力。我们假设CSPG和PTEN是CNS神经元再生失败的关键因素，并且对两种抑制的结合促进促进轴突再生，而不是单独抑制任何一种。我们建议解决以下3个特定目的：1）确定两个CSPG受体的转基因缺失或肽阻塞是否在SCI的成年小鼠中产生更好的轴突生长，而在体内和功能恢复量是否比单独抑制任何一个受体的轴突恢复； 2）确定使用肽的PTEN阻断是否会刺激相似的刺激，确定与单独阻断任何一个单独阻断SCI后，SCI后CSPG信号传导和PTEN是否同时促进了SCI后更大的轴突再生和行为恢复。将肽治疗的结果与转基因小鼠实验的结果进行比较。我们单独或联合使用小型化合物的新型策略可能有助于开发用于中枢神经系统损伤的实用疗法。