NGF effects on axonal growth in CNS white matter

描述（由申请人提供）：轴突再生现已被证明发生在以前认为不可能发生的中枢神经系统区域。这些成功再生的戏剧性例子来自于研究神经突生长抑制剂和促进剂的影响。近年来视神经再生的研究证实了神经元生长状态对再生成功的重要性。总的来说，这些结果指出了通常刺激生长的因素在克服中枢神经系统白质不允许的特征中的重要性。这里提出的工作将利用该实验室多年来开发的技术，这些技术允许评估NGF在刺激中枢神经系统轴突生长中的作用。在星形胶质细胞特异性启动子（GFAP）的控制下，NGF过表达的转基因小鼠将用于体外和体内中枢神经系统白质轴突生长的研究。将对这些小鼠的中枢神经系统区域内的交感神经轴突生长进行体内研究，以确定NGF的异位表达在多大程度上改变了这些异常纤维的生长。此外，组织切片培养研究将进行，以确定无论是外源应用还是转基因表达的NGF，是否会改变中枢神经系统白质支持轴突生长的一般不允许性质。最后，我们将通过一系列移植和组织培养方法研究低亲和力NGF受体p75在中枢神经系统白质中调节NGF反应神经元轴突生长中的作用，这些方法使用的是缺乏NGF过表达的转基因小鼠p75。主要目的是研究神经营养因子在刺激中枢神经系统白质轴突再生中的作用。

DESCRIPTION (provided by applicant): Axonal regeneration has now been demonstrated to occur in regions of the CNS where it was formerly thought to be impossible. These dramatic examples of successful regrowth have come from studies in which the influence of both inhibitors and promoters of neurite growth have been examined. The importance of neuronal growth state on regeneration success has recently been demonstrated in studies of optic nerve regeneration. Collectively, these results point to the importance of factors that normally stimulate growth in overcoming the non-permissive features of CNS white matter. The work proposed here will take advantage of techniques that have been developed in this laboratory over several years that permit assessment of the role of NGF in stimulating axonal growth within the CNS. Transgenic mice in which NGF is over-expressed under the control of an astrocyte-specific promoter (GFAP), will be used for both in vitro and in vivo studies of axonal growth in CNS white matter. In vivo studies of sympathetic axonal growth within CNS regions of such mice will be carried out to determine the extent to which ectopic expression of NGF modifies the growth of these aberrant fibers. In addition, tissue section culture studies will be carried out to determine whether NGF, either applied exogenously or expressed transgenically, will modify the generally non-permissive nature of CNS white matter in supporting axonal growth. Finally, the role of p75, the low-affinity NGF receptor, in modifying axonal growth of NGF-responsive neurons in CNS white matter will be studied through a series of transplant and tissue culture approaches using transgenic mice in which p75 is deficient in the presence of NGF overexpression. The primary goal is to study the role of neurotrophic factors in stimulating axonal regeneration within CNS white matter.