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.
Peripheral nerve injuries and neuropathies afflict millions of people in the United States, often producing disabling symptoms of weakness, numbness or pain. Peripheral nerves have the capacity to regenerate, but unfortunately, the regeneration is too slow and insignificant in most cases to produce meaningful recovery. Nerve regeneration requires significant energy, and increasing the supply of energy to nerves through lactate transporters, as described in this proposal, has the potential to accelerate nerve regeneration and ameliorate the symptoms of patients with nerve injury or neuropathies.
| Jha, Mithilesh Kumar; Morrison, Brett M (2018) Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters. Exp Neurol 309:23-31 |
