Genetic analysis of myelin inhibitors and PTEN in injury-inducedCNS axon growth

描述（由申请人提供）：成年哺乳动物中枢神经系统（CNS）轴突再生能力差是脊髓损伤、创伤性脑损伤、白质中风和某些神经退行性疾病后功能恢复有限的原因。有两种形式的损伤诱导的轴突生长可能有助于功能修复：损伤轴突的再生和未损伤轴突的代偿生长（或发芽）。本应用的目的是为了更好地理解分子参与者在轴突发芽和再生中的作用，包括中枢神经系统环境中的外在因素和神经元中的内在因素。该研究将重点关注由中枢神经系统髓磷脂（Nogo, OMgp）和PTEN（神经元内在生长潜能的负调节因子）产生的两种轴突生长抑制剂。总体方法是研究缺乏一种或多种生长调节剂的小鼠轴突对损伤的反应，以便评估这些蛋白质的正常功能。目的1将确定Nogo在皮质脊髓束（CST）轴突发芽中起重要作用的细胞类型，Nogo和OMgp是否协同作用以阻止CST轴突发芽，并将进一步探索这种增强发芽与康复的功能后果。Aim 2将确定靶向髓磷脂抑制剂和PTEN对脊髓轴突发芽和再生的联合作用，以及轴突生长的增强是否会导致突触的形成和功能恢复。该建议利用小鼠遗传学的力量来确定特定的内在和外在调节因子的作用，并可能对这些分子在损伤诱导的轴突生长中的功能产生重要的见解。更好地了解成人中枢神经系统损伤诱导的轴突生长的分子决定因素对于设计包括脊髓损伤在内的各种神经系统疾病的有效治疗策略至关重要。

DESCRIPTION (provided by applicant): The poor regenerative ability of axons in the adult mammalian central nervous system (CNS) underlies the limited functional recovery following spinal cord injury, traumatic brain injury, white matter stroke and certain neurodegenerative disorders. There are two forms of injury-induced axonal growth that may contribute to functional repair: regeneration of injured axons and compensatory growth (or sprouting) of uninjured axons. The goal of this application is to gain a better understanding of the role of the molecular players - both extrinsic factors in the CNS environment and intrinsic factors in the neurons - in axon sprouting and regeneration. The study will focus on two inhibitors of axon growth made by the CNS myelin (Nogo, OMgp) and PTEN, a negative regulator of neuron-intrinsic growth potential. The overall approach is to study the responses of axons to injury in mice lacking one or more growth regulators so the normal function of these proteins can be assessed. Aim 1 will determine the cell type that is important for the role of Nogo in axon sprouting of the corticospinal tract (CST), whether Nogo and OMgp synergize to prevent CST axon sprouting, and will further explore the functional consequences of such enhanced sprouting in conjunction with rehabilitation. Aim 2 will determine the combined effect of targeting the myelin inhibitor(s) and PTEN on spinal axon sprouting and regeneration, and whether enhanced axonal growth leads to synapse formation and functional recovery. The proposal takes advantage of the power of mouse genetics to pinpoint the role of specific intrinsic and extrinsic regulators and will likely yield important insights on the functions of these molecules in injury-induced axonal growth. A better understanding of the molecular determinants of injury-induced axonal growth in the adult CNS is crucial to the design of effective therapeutic strategies for various neurological conditions including spinal cord injury.