Sox11 and Functional Recovery of Sensory Neurons

描述：在发育过程中发现转录因子sox11表达增强。 转基因小鼠三叉神经节和背根神经节感觉神经元的过度表达 皮肤中的神经营养生长因子。这一表达表明Sox11在转录水平上 皮肤增强神经元存活和轴突投射的调控基因 这些动物的感觉神经元。在成人DRG中，sox11的表达水平较低，但表现为 在周围神经挤压后显著增加。Sox11的高水平表达 成年神经元损伤后的发育和提示Sox11调节一组特定的基因， 在神经元存活和轴突生长中起着至关重要的作用。这项提议的实验将开始 确定sox11可能的作用靶点并确定其在成年神经元中的表达 调节它们的存活、轴突生长和反应特性。提出了三个具体目标。 AIM 1将使用荧光素酶报告分析来测试已识别的与生存和轴突有关的目标基因 生长受sox11基因表达的调控。目标2将检查Sox11在 DRG培养或活体神经损伤后与解剖和修复的速度和质量相关 功能恢复。在这些研究中，我们将使用两种方法来操纵Sox11水平。至 减少DRG神经元的表达，我们将使用RNAi方法。增加sox11的表达 我们将使用非复制的、嗜神经的单纯疱疹病毒病毒载体。Sox11水平的变化可能会改变 可能导致行为的传入敏感性和疼痛信号相关基因的表达 敏感度。目标3将通过测量对施加的热和热的行为反应来测试这种可能性 机械刺激。与公共卫生相关：神经损伤后恢复受损可能对 由于神经功能异常或持续疼痛而导致的个人的生活质量和生产力 在受伤之后。提高对细胞和分子机制的理解 创伤后神经元的存活和功能恢复是设计有效的 复苏战略。

Description: Enhanced expression of the transcription factor Sox11 was identified in developing sensory neurons of trigeminal and dorsal root ganglia of transgenic mice that overexpress neurotrophic growth factors in the skin. This expression suggested that Sox11 transcriptionally regulate genes involved in the enhanced neuron survival and axon projections exhibited by cutaneous sensory neurons in these animals. In adult DRG Sox11 was expressed at a low level but showed a significant increase following peripheral nerve crush. The high level of Sox11 expression during development and following adult neuron injury suggests Sox11 modulates a specific set of genes that have essential roles in neuron survival and axon growth. The experiments of this proposal will begin to define putative targets of Sox11 action and determine how its expression in adult neurons modulates their survival, axonal growth and response properties. Three specific aims are proposed. Aim 1 will use luciferase reporter assays to test if identified target genes involved in survival and axon growth are modulated by Sox11 expression. Aim 2 will examine if the level of Sox11 expression in DRG cultures or following in vivo nerve injury correlates with the rate and quality of anatomical and functional recovery. In these studies we will manipulate Sox11 level using two approaches. To decrease expression in DRG neurons we will use a RNAi approach. To increase expression of Sox11 we will use non-replicating, neurotropic HSV viral vectors. Changes in Sox11 level may alter expression of genes involved in afferent sensitivity and pain signaling which could lead to behavioral sensitivity. Aim 3 will test this possibility by measuring behavioral responses to applied thermal and mechanical stimuli. Relevance to Public Health: Impaired recovery following nerve injury can have significant effects on the quality of life and productivity of an individual due to abnormal nerve function or persistent pain following injury. Improved understanding of the cellular and molecular mechanisms that underlie survival and functional recovery of neurons following traumatic injury is required for design of effective strategies for recovery.