Sox11 and Functional Recovery of Sensory Neurons

描述：转录因子Sox 11的增强表达在发育中被鉴定， 三叉神经和背根神经节的感觉神经元的转基因小鼠， 皮肤中的神经营养生长因子。这种表达表明Sox 11在转录水平上 调节基因参与增强神经元存活和轴突投射表现出皮肤 这些动物的感觉神经元。在成人DRG中，Sox 11表达水平较低，但在成人DRG中， 在周围神经挤压后显著增加。Sox11在细胞内的高水平表达， 发育和成年神经元损伤后表明Sox 11调节一组特定的基因， 在神经元存活和轴突生长中起着重要作用。这个提议的实验将开始 确定Sox 11作用的假定靶点，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基因分析来测试是否识别出参与存活和轴突生长的靶基因。 生长受到Sox11表达的调节。目的2将检测Sox11表达水平是否与Sox12表达水平相关。 DRG培养物或体内神经损伤后的DRG培养物与解剖学和病理学检查的速率和质量相关。 功能恢复在这些研究中，我们将使用两种方法操纵Sox 11水平。到 为了减少DRG神经元中的表达，我们将使用RNAi方法。增加Sox11的表达 我们将使用非复制型嗜神经性HSV病毒载体。Sox11水平的变化可能会改变 参与传入敏感性和疼痛信号的基因表达，这可能导致行为 灵敏度目标3将测试这种可能性，通过测量行为的反应， 机械刺激与公共卫生的相关性：神经损伤后的恢复受损可能会对神经功能产生重大影响。 由于神经功能异常或持续疼痛而导致的个人生活质量和生产力 受伤后。更好地理解细胞和分子机制， 创伤性损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.