Role of Monocarboxylate Transporters in the Recovery from Peripheral Nerve Injury

 描述(申请人提供)：周围神经损伤和周围神经病变是常见的疾病，通过麻木、虚弱、疼痛或自主功能衰竭的发展而导致显著的长期发病率和残疾。虽然神经损伤和神经病变的病因很多，但大多数最终会导致垂死性的远端轴突变性。因此，周围神经治疗的一个主要目标是促进和加速轴突再生。周围神经有很高的能量需求来维持电化学梯度和轴突运输，在损伤后的再生过程中，这些需求急剧增加，因为周围神经合成了被雪旺细胞和巨噬细胞降解的轴突和髓鞘成分，并将它们运送到再生的轴突下。尽管这些过程的一些代谢能量可能是由葡萄糖提供的，但有证据表明，神经也需要局部产生的乳酸来支持轴突功能。我们假设，在周围神经挤压、丙烯酰胺或紫杉醇诱导的神经病后，单羧酸转运体(MCTs)是向再生轴突和雪旺细胞供应乳酸所必需的，MCTs的减弱将减缓再生速度，而MCTs的上调将加速再生。这将在三个具体目标中进行评估。在第一个目标中，将在神经周围或雪旺细胞内选择性衰减MCT1后评估坐骨神经挤压后的神经再生。在第二个目标中，神经挤压后的神经再生将在神经周围或雪旺细胞中MCT1上调后进行评估。在第三项，也是最后一项中，将评估MCT1的上调和下调在毒素或化疗引起的周围神经病变的发生和恢复中的作用。在所有目标中，神经再生将通过电生理学、病理学和行为评估来量化。这些实验是MCT在周围神经再生中的首次完成，将确定MCT1对神经再生是否重要，这是对其功能至关重要的特定细胞类型，并为基于MCT生物学的周围神经损伤和神经疾病的新疗法的开发提供基础。

 DESCRIPTION (provided by applicant): Peripheral nerve injuries and peripheral neuropathies are common diseases that produce significant long-term morbidity and disability through the development of numbness, weakness, pain or autonomic failure. Though there are many etiologies for nerve injury and neuropathies, most ultimately produce dying-back distal axonal degeneration. Thus, a major goal for peripheral nerve treatments is to promote and accelerate axon regeneration. Peripheral nerves have high energy requirements in order to maintain electrochemical gradients and axonal transport, and these demands increase dramatically during regeneration following injury as peripheral nerves synthesize the axonal and myelin components degraded by Schwann cells and macrophages and transport them down the regrowing axons. Though some of the metabolic energy for these processes is likely provided by glucose, evidence is emerging that nerves also require locally produced lactate to support axon function. We hypothesize that monocarboxylate transporters (MCTs) are necessary for the supply of lactate to regenerating axons and Schwann cells and that attenuation of MCTs will slow regeneration, while upregulation of MCTs will accelerate regeneration, following peripheral nerve crush, acrylamide-induced or paclitaxel-induced neuropathy. This will be evaluated in three Specific Aims. In the first Aim, nerve regeneration following sciatic nerve crush will be evaluated following selective attenuation of MCT1 within perineurial or Schwann cells. In the second Aim, nerve regeneration following nerve crush will be evaluated following upregulation of MCT1 in perineurial or Schwann cells. In the third, and final, Aim, up- and down- regulation of MCT1 will be evaluated in the development and recovery from peripheral neuropathy induced by toxins or chemotherapies. In all Aims, nerve regeneration will be quantified by electrophysiology, pathology, and behavioral assessments. These experiments, which are the first completed of MCTs in peripheral nerve regeneration, will determine whether MCT1 is important for nerve regeneration, the specific cell-types critical for their function, and provide he backbone for the development of new therapies for peripheral nerve injury and neuropathies based on MCT biology.