Role of Monocarboxylate Transporters in the Recovery from Peripheral Nerve Injury

 描述（由申请人提供）：周围神经损伤和周围神经病是常见疾病，通过麻木、虚弱、疼痛或自主神经功能衰竭的发展产生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，但大多数最终导致远端轴突退行性变。因此，周围神经治疗的主要目标是促进和加速轴突再生。外周神经具有高能量需求以维持电化学梯度和轴突运输，并且这些需求在损伤后的再生期间显著增加，因为外周神经合成由雪旺细胞和巨噬细胞降解的轴突和髓鞘组分并将它们沿着再生轴突运输。虽然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，单羧酸转运蛋白（MCT）是必要的乳酸再生轴突和雪旺细胞的供应和MCT的衰减将减缓再生，而上调的MCT将加速再生，周围神经挤压，丙烯酰胺诱导或紫杉醇诱导的神经病变。这将在三个具体目标中进行评估。在第一个目标中，将在神经束膜或雪旺细胞内选择性衰减MCT 1后评价坐骨神经挤压后的神经再生。在第二个目标中，将在神经束膜或许旺细胞中的MCT 1上调后评价神经挤压后的神经再生。在第三个也是最后一个目标中，将在毒素或化疗诱导的周围神经病变的发展和恢复中评价MCT 1的上调和下调。在所有目的中，将通过电生理学、病理学和行为评估对神经再生进行量化。这些实验是首次完成的MCT在周围神经再生中的实验，将确定MCT 1是否对神经再生重要，对它们的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病的新疗法的开发提供支柱。

 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.