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（由申请人提供）：通过使用PI实验室开发的新型全身可递送的小抑制肽，我们旨在确定靶向细胞外抑制因子和神经元内源性因子是否可以显著改善脊髓损伤（SCI）后的轴突再生和功能恢复。由于外部抑制环境和成熟神经元内在生长能力的降低，切断的CNS轴突不能再生。由胶质瘢痕产生的硫酸软骨素蛋白聚糖（CSPG）强烈抑制轴突延伸进入和超出损伤区域，并且是治疗SCI的主要分子靶点。最近，我们和其他实验室鉴定了LAR和PTP？磷酸酶作为介导CSPG抑制的受体。删除其中任何一个刺激脊髓损伤后轴突生长。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CNS轴突的内在再生能力。因此，抑制CSPG受体和PTEN有望促进CNS损伤后的轴突再生。我们已经设计了小肽，通过靶向它们的特定结构域来阻断这些抑制分子的功能，并证明了我们的肽在体外和体内促进轴突生长的高功效。由于CSPGs和PTEN似乎通过不同的信号传导途径限制生长，因此两者的抑制可以协同作用，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来促进轴突再生。我们假设CSPGs和PTEN是CNS神经元再生失败的关键因素，两者的联合抑制比单独抑制任何一个更好地促进轴突再生。我们提出了以下3个具体目的：1）确定两种CSPG受体的转基因缺失或肽阻断是否在SCI成年小鼠中产生比单独抑制任一受体更好的体外和体内轴突生长和功能恢复; 2）确定用肽阻断PTEN是否在体外和体内刺激与转基因PTEN缺失相似程度的轴突生长和功能恢复; 3）确定用肽阻断CSPG信号传导和PTEN两者是否比单独阻断任一者促进SCI后更大的轴突再生和行为恢复。将肽处理的结果与转基因小鼠实验的结果进行比较。我们的新策略，给药小化合物全身单独或组合可能有助于开发一个实用的治疗中枢神经系统损伤。