Cellular and molecular mechanisms of peripheral sensory neuron regeneration

描述（由申请人提供）：由于疾病或创伤引起的周围神经变性可导致永久性无力，麻木或慢性疼痛等严重残疾。更好地了解外周轴突再生和神经再生的细胞和分子机制可能会导致改进的治疗策略。本文提出了一种以斑马鱼三叉神经为模型，横切单个轴突，在体内直接观察外周靶神经再生细胞动力学的方法。该技术用于定量表征野生型再生在几个发育阶段。本研究的总体目标是确定参与外周目标神经再生的细胞和分子机制。野生型动物的神经再生特征将作为比较各种斑马鱼突变体和药物治疗效果的基线。这项工作可能会发现新的分子靶点，可以用于治疗人类周围神经病变。该项目的具体目标概述如下。目的1)通过特异性确定Rho通路何时、何地以及如何介导神经再生抑制来研究单个损伤轴突的细胞内信号传导。目的2)利用斑马鱼突变体和药物操作来确定调节神经再生能力的外在因素。这一目标特别关注吞噬细胞、外周胶质细胞、细胞外基质成分和炎症反应的作用。

DESCRIPTION (provided by applicant): Peripheral nerve degeneration due to disease or trauma can result in serious disability from permanent weakness, numbness or chronic pain. A better understanding of the cellular and molecular mechanisms of peripheral axon regeneration and reinnervation may lead to improved treatment strategies. This proposal describes a method to transect individual axons and directly observe the cellular dynamics of peripheral target reinnervation in vivo, using zebrafish trigeminal neurons as a model. This technique was used to quantitatively characterize wildtype regeneration at several developmental stages. The overall objective of the proposed research is to define the cellular and molecular mechanisms involved in reinnervation of peripheral targets. The characterization of reinnervation in wildtype animals will serve as a baseline to compare the effects of various zebrafish mutants and pharmacological treatments. This work may identify novel molecular targets that can be exploited for therapeutic purposes in peripheral neuropathy in humans. The specific goals of the project are outlined below. Aim 1) To investigate intracellular signaling in individual injured axons by specifically determining when, where, and how the Rho pathway acts to mediate inhibition of reinnervation. Aim 2) To identify extrinsic factors that modulate the capacity for reinnervation using zebrafish mutants and pharmacological manipulations. This aim specifically focuses on the role of phagocytic cells, peripheral glia, the extra cellular matrix components, and the inflammatory response.