Mechanisms of Preferential Reinveration

描述（由申请人提供）：神经损伤每年损害超过80,000美国人的功能。令人惊讶的是，神经损伤的治疗，外科手术恢复神经的连续性，在上个世纪几乎没有变化。促进神经再生的因素的发现刺激了各种动物模型的实验。尽管这项工作很有前景，然而，我们仍然缺乏准确的知识，哪些因素促进体内特定轴突群体的再生。该建议扩展了我们实验室正在进行的工作，以提供这方面的知识。我们已经证明，髓鞘周围神经的雪旺细胞，曾经被认为表达单一表型，在其生长因子表达方面差异很大。此外，这些特化的雪旺细胞优先支持其原生轴突群体的再生。我们现在建议确定哪些在感觉和运动神经中表达差异的因子负责选择性促进感觉和运动轴突再生。分析将从不同类型移植物中生长因子浓度与其促进感觉或运动再生能力的相关性开始。我们设计了一种新颖的体外神经修复技术，它与体内修复技术非常相似，并将利用这种技术来观察增强或消除特定因素的功能的效果。然后在体内对雪旺细胞进行修饰，通过慢病毒载体转染或DNA质粒电穿孔来增加有希望因子的表达。在大鼠正中神经移植后，通过测量其对模式功能和自主功能恢复的影响来评估最有效的生长因子。确定最佳感觉和运动轴突再生所需的特定因素将对神经修复、神经移植和使用雪旺细胞促进脊髓再生具有直接和立即的临床意义。一个多世纪以来，皮神经移植用于神经重建，通常效果不佳。我们最近的研究表明，皮肤神经和肌肉神经在其生长因子产生方面存在显著差异，并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对这种特异性负责，并将制定策略，利用这些因子来改善神经修复和重建的结果，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.