Mechanisms of Preferential Reinveration

描述（由申请人提供）：每年有超过 80,000 名美国人因神经损伤而丧失功能。令人惊讶的是，神经损伤的治疗、粗大神经连续性的手术恢复，在上个世纪几乎没有变化。促进神经再生因子的发现刺激了各种动物模型的实验。然而，尽管这项工作很有前景，我们仍然缺乏关于哪些因素促进体内特定轴突群再生的精确知识。该提案扩展了我们实验室正在进行的工作以提供这些知识。我们已经表明，曾经被认为表达单一表型的有髓鞘周围神经的雪旺细胞，其生长因子表达差异很大。此外，这些特化的雪旺细胞优先支持其天然轴突群体的再生。我们现在建议确定哪些在感觉和运动神经中差异表达的因子负责选择性促进感觉和运动轴突再生。分析将从各种类型移植物中生长因子浓度与其促进感觉或运动再生的能力的相关性开始。我们设计了一种体外神经修复的新技术，它与体内修复非常相似，并将用它来观察增强或消除特定因子功能的效果。然后，通过用慢病毒载体转染雪旺细胞或用 DNA 质粒对其进行电穿孔，对雪旺细胞进行体内修饰，以增加有希望的因子的表达。通过测量神经移植后对模式和随意功能恢复的影响，对大鼠正中神经中最有效的生长因子进行评估。识别最佳感觉和运动轴突再生所需的具体因素将对神经修复、神经移植和使用雪旺细胞促进脊髓再生具有直接和直接的临床意义。公共卫生相关性 一个多世纪以来，皮神经移植物一直被用于神经重建，但效果往往不佳。我们最近的工作表明，皮肤神经和肌肉神经在生长因子的产生方面存在显着差异，并且在特定模式的基础上支持再生。拟议的实验将确定哪些生长因子导致这种特异性，并将设计利用这些因子来改善神经修复和重建结果的策略，每年可能帮助数千名患者。

DESCRIPTION (provided by applicant): Nerve injury compromises the function of over 80,000 Americans each year. Surprisingly, the treatment of nerve injury, surgical restoration of gross nerve continuity, has changed little in the last century. The discovery of factors that promote nerve regeneration has stimulated experimentation in a variety of animal models. In spite of this promising work, however, we still lack precise knowledge of which factors promote the regeneration of specific axon populations in vivo. This proposal extends work ongoing in our laboratory to provide this knowledge. We have shown that Schwann cells of myelinating peripheral nerve, once thought to express a single phenotype, vary widely in their growth factor expression. Furthermore, these specialized Schwann cells preferentially support the regeneration of their native axon population. We now propose to determine which of the factors expressed differentially in sensory and motor nerve are responsible for selective promotion of sensory and motor axon regeneration. Analysis will begin with correlation of growth factor concentration in various types of graft with their ability to promote sensory or motor regeneration. We have devised a novel technique of nerve repair in vitro that closely mimics repair in vivo, and will use this to observe the effects of augmenting or eliminating the function of specific factors. Schwann cells will then be modified in vivo to increase the expression of promising factors by transfecting them with lentiviral vectors or electroporating them with DNA plasmids. The most effective growth factors will be evaluated in the rat median nerve by measuring their impact on recovery of patterned and voluntary function after nerve grafting. Identification of the specific factors needed for optimal sensory and motor axon regeneration will have direct and immediate clinical implications for nerve repair, nerve grafting, and the use of Schwann cells to promote spinal cord regeneration. PUBLIC HEALTH RELEVANCE For over a century graft of cutaneous nerve has been used for neural reconstruction, often with poor results. Our recent work has shown that cutaneous and muscle nerves differ significantly in their growth factor production, and support regeneration on a modality-specific basis. The proposed experiments will determine which growth factors are responsible for this specificity, and will devise strategies for using these factors to improve the outcome of nerve repair and reconstruction, potentially helping thousands of patients a year.