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(申请人提供)：通过使用PI实验室开发的新的、系统可释放的小抑制性多肽，我们的目标是确定同时针对细胞外抑制因子和神经元内部因子是否能够显著促进脊髓损伤(SCI)后轴突的再生和功能恢复。由于外在的抑制环境和成熟神经元内在生长能力的降低，切断的中枢神经系统轴突无法再生。胶质瘢痕产生的硫酸软骨素蛋白多糖(CSPGs)强烈抑制轴突伸展进入和超出损伤区域，是治疗脊髓损伤的主要分子靶点。最近，我们和其他实验室确定LAR和PTP？磷酸酶是介导CSPG抑制的受体。其中任何一个的缺失都会刺激脊髓损伤后轴突的生长。最近使用条件性基因敲除小鼠的研究表明，PTEN严重限制了受损中枢神经系统轴突的内在再生能力。因此，抑制CSPG受体和PTEN有望促进中枢神经系统损伤后轴突的再生。我们设计了小肽，通过靶向这些抑制分子的特定结构域来阻断它们的功能，并在体外和体内证明了我们的多肽在促进轴突生长方面的高效。由于CSPGs和PTEN似乎通过不同的信号通路限制生长，因此两者的抑制可能通过减少损伤部位的环境抑制影响和增强成熟神经元的内在生长能力而协同作用，促进轴突再生。我们假设CSPG和PTEN是中枢神经系统神经元再生失败的关键贡献者，并且两者联合抑制比单独抑制两者之一更能促进轴突再生。我们建议解决以下3个特定目标：1)确定转基因缺失或多肽阻断两个CSPG受体的转基因在体内外和成年脊髓损伤小鼠中的轴突生长和功能恢复是否比单独抑制其中一个受体更好；2)确定多肽阻断PTEN在体内外是否能刺激与转基因PTEN缺失相似的轴突生长和功能恢复；3)确定多肽同时阻断CSPG信号和PTEN是否比单独阻断其中一个促进脊髓损伤后更大的轴突再生和行为恢复。多肽治疗的结果将与转基因小鼠实验的结果进行比较。我们系统地单独或联合应用小分子化合物的新策略可能有助于开发一种治疗中枢神经系统损伤的实用疗法。