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CNS区域。这些戏剧性的成功再生的例子来自于研究，在这些研究中，神经突生长的抑制剂和促进剂的影响已经被检查。神经元生长状态对再生成功的重要性最近在视神经再生的研究中得到证实。总的来说，这些结果指出了通常刺激生长的因素在克服CNS白色物质的非允许特征方面的重要性。 这里提出的工作将利用本实验室几年来开发的技术，该技术允许评估NGF在刺激CNS内轴突生长中的作用。在星形胶质细胞特异性启动子（GFAP）的控制下过度表达NGF的转基因小鼠将用于CNS白色物质中轴突生长的体外和体内研究。将进行这些小鼠CNS区域内交感神经轴突生长的体内研究，以确定NGF的异位表达改变这些异常纤维生长的程度。 此外，将进行组织切片培养研究，以确定外源性应用或转基因表达的NGF是否会改变CNS白色物质在支持轴突生长方面的通常不允许的性质。 最后，p75的作用，低亲和力的神经生长因子受体，在修改轴突生长的神经生长因子反应神经元在中枢神经系统白色的问题将通过一系列的移植和组织培养的方法使用转基因小鼠，其中p75是缺乏的存在下，神经生长因子过表达进行研究。 主要目的是研究神经营养因子在刺激中枢神经系统白色物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.