Sox11 and Functional Recovery of Sensory Neurons

Sox11 和感觉神经元的功能恢复

• 批准号: 7991798
• 负责人: Kathryn Marie Albers
• 金额: $ 32.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991798
• 关键词: Abbreviations; Accounting; Address; Adult; Affect; Afferent Neurons; Animals; Apoptotic; Axon; Axotomy; BDNF gene; Behavioral; Binding; Binding Sites; Biological Assay; Boxing; Brain-Derived Neurotrophic Factor; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Characteristics; Ciliary Neurotrophic Factor; Cleaved cell; Complication; Consensus; Critiques; Crush Injury; Cutaneous; Data; Data Reporting; Deletion Mutagenesis; Development; Dissociation; Electrons; Exhibits; Family; GDNF gene; Gene Expression; Gene Targeting; Gene Transfer; Genes; Glutamates; Goals; Growth; Growth Factor; Growth Factor Overexpression; Growth Factor Receptors; In Vitro; Individual; Injection of therapeutic agent; Injury; JUN gene; Knockout Mice; Knowledge; Lead; Length; Link; Luciferases; Mechanics; Mediating; Messenger RNA; Microarray Analysis; Microscopic; Molecular; Motor; Motor Neurons; Mus; Natural regeneration; Nerve; Nerve Crush; Nerve Regeneration; Neurites; Neuroglia; Neuronal Injury; Neurons; Nucleic Acid Regulatory Sequences; Pain; Pathway interactions; Peptides; Peripheral; Peripheral Nerves; Peripheral nerve injury; Persistent pain; Physiological; Principal Investigator; Productivity; Property; Proteins; Public Health; Publishing; Quality of life; RNA Interference; Receptor Signaling; Recovery; Recovery of Function; Regulation; Reporter; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Schwann Cells; Sensory; Sensory Ganglia; Signal Transduction; Simplexvirus; Site; Skin; Small Interfering RNA; Spinal Cord; Spinal Ganglia; Staining method; Stains; Stimulus; Stress; Supporting Cell; System; Testing; Time; Transfection; Transgenic Mice; Translational Repression; Trigeminal System; Up-Regulation; Viral Vector; Work; activating transcription factor 3; axon growth; axon regeneration; behavior measurement; caspase-3; central pain; central sensitization; conditioning; design; dorsal horn; excitatory neuron; improved; in vivo; injured; interest; knock-down; member; nerve injury; neurite growth; neuronal cell body; neurotropic; overexpression; penetratin; presynaptic; profilin; programs; promoter; protective effect; research study; response; spatial relationship; transcription factor

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.

描述：在开发中确定了转录因子SOX11的增强表达 过表达的转基因小鼠的三叉神经神经节的感觉神经元 皮肤中的神经营养生长因子。该表达表明Sox11在转录上 调节皮肤表现出的增强神经元存活和轴突投射涉及的基因 这些动物中的感觉神经元。在成年DRG中，Sox11在低水平上表达，但显示出 周围神经压伤后大幅增加。高水平的Sox11表达 开发和遵循成年神经元损伤表明Sox11调节了一组特定的基因 在神经元存活和轴突生长中具有重要作用。该提案的实验将开始 定义Sox11动作的推定靶标，并确定其在成年神经元中的表达方式 调节其存活率，轴突生长和反应特性。提出了三个具体目标。 AIM 1将使用萤光素酶报告基准测定法测试是否鉴定出与生存和轴突有关的靶基因 生长由Sox11表达调节。 AIM 2将检查Sox11表达的水平是否在 DRG培养或遵循体内神经损伤与解剖学的速度和质量相关 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。到 降低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神经性HSV病毒载体。 Sox11级别的变化可能会改变 表达参与传入灵敏度和疼痛信号传导的基因，这可能导致行为 灵敏度。 AIM 3将通过测量对施加的热量的行为响应来测试这种可能性 机械刺激。与公共卫生有关：神经损伤后的康复受损可能对 由于神经功能异常或持续性疼痛，个人的生活质量和生产力 受伤后。对基础的细胞和分子机制的了解得以提高 创伤后的神经元的生存和功能恢复是有效设计的 恢复策略。