Role of RAGE signalling in peripheral nerve regeneration and in mediating the neurotrophic effects of the HNK-1 carbohydrate

尽管外周神经系统中的再生通常不被抑制，如在成年哺乳动物的中枢神经系统中那样，但由于不完全或错误靶向的问题，人类的神经修复通常是不充分的。优先运动神经支配的股神经已在我们的研究中的运动神经元寻路的准确性和揭示的分子决定因素，这种优先再生长到正确的分支的股神经在股神经分叉的选择点。我们建议通过扰动实验在成年小鼠中研究优先运动神经再支配，通过测试晚期糖基化终末产物受体（AGEs）（AGEs）的应用结果，AGEs是AGEs的受体，AGEs又与成年小鼠中的HNK-1碳水化合物结合。这种碳水化合物及其糖模拟物被我们证明是有助于增强优先运动神经再支配的小鼠。我们还将测试成年小鼠的再生，这些小鼠在遗传上缺乏再生能力。还将在Thy-1启动子控制下表达显性负调控基因的转基因小鼠中测试再生。由于脑源性神经营养因子及其同源受体参与HNK-1碳水化合物表达的调节，我们将尝试通过将HNK-1糖模拟物应用于这些突变小鼠的受损股神经来规避股神经切断后HNK-1上调的缺陷。结合实验应该产生的优先运动神经再支配的分子机制的见解，希望将这些知识转化为灵长类动物的治疗有价值的方法。

Although regeneration in the peripheral nervous system is not generally inhibited, as it is in the central nervous system of adult mammals, nerve repair in humans are often not adequate due to the problem of incomplete or faulty targeting. Preferential motor reinnervation of the femoral nerve has been paradigmatic in our studies on the accuracy of motoneuron pathfinding and uncovering the molecular determinants of this preferential regrowth of motor axons into the correct branch of the femoral nerve at the choice point where the femoral nerve bifurcates. We propose to investigate preferential motor reinnervation by perturbation experiments in adult mice by testing the outcome of application of the receptor for advanced glycation end products (RAGE), which is a receptor for amphoterin, which in turn binds to the HNK-1 carbohydrate in adult mice. This carbohydrate and its glycomimetic were shown by us to be instrumental in enhancing preferential motor reinnervation in the mouse. We will also test regeneration in adult mice that are genetically deficient in RAGE. Regeneration will also be tested in transgenic mice that express dominant-negative RAGE under the control of the Thy-1 promoter. Since the brain-derived neurotrophic factor and its cognate receptor are involved in regulation of HNK-1 carbohydrate expression, we will try to circumvent deficiency in HNK-1 upregulation after femoral nerve transection by applying the HNK-1 glycomimetic to the injured femoral nerve of these mutant mice. The combined experiments should yield insights into the molecular mechanisms of preferential motor reinnervation with the hope to translate this knowledge into a therapeutically valuable approach in primates.