Molecular Mechanisms of Axonal Regeneration

轴突再生的分子机制

• 批准号: 7282036
• 负责人: Hongyan Zou
• 金额: $ 5.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282036
• 关键词: Acute; Axotomy; Biological Assay; Cis Golgi network; Complex; Environment; Epidermal Growth Factor Receptor; Failure; Gene Silencing; Genetic Epistasis; Growth; Homologous Gene; Knock-out; Lesion; Mediating; Molecular; Mus; Mutant Strains Mice; Mutation; Myelin; NGFR Protein; Natural regeneration; Neuraxis; Neurites; Neurons; Pathway interactions; Peripheral; Protein Overexpression; RNA Interference; Role; Signal Transduction; Sindbis Virus; Spinal; Spinal Ganglia; Testing; Transfection; axon regeneration; dorsal column; gain of function; granule cell; loss of function; receptor; transcription factor; transcriptional coactivator p75

DESCRIPTION (provided by applicant): The failure of axonal regeneration in mammalian central nervous system is attributed to hostile environment from myelin and the diminished instrinsic regenerative capacity of mature neurons. Axotomy of the peripheral branches of dorsal root ganglion neurons results in robust regeneration such that they can regenerate their central branches in lesioned spinal dorsal column. The roles of three transcription factors ATF3, Stat3 and Smad1 will be studied by using RNA interference for acute gene-silencing and Sindbis virus for overexpression. To dissect the molecular pathways involved in mediating myelin inhibition, the possibly redundant roles of p75 and TROY, NgR1 and its homologues NgR2 and NgR3 will be investigated by conducting myelin inhibition assays on dissociated neurons and explants of both dorsal root ganglion and cerebellar granule cells from wild-type, p75-/-, TROY-/-, NgR-/- mice or double mutant mice. RNA interference will be used for multiple knockdown. Epistasis analysis will be conducted to study the pathway relationships between the p75/NgR receptor complex and epidermal growth factor receptor (EGFR). Such understanding can help elucidate mechanisms of both intrinsic growth state and extrinsic myelin inhibition.

描述（由申请人提供）：哺乳动物中枢神经系统中轴突再生的失败归因于髓磷脂的不利环境和成熟神经元的内在再生能力的减弱。背根神经节神经元外周分支的轴切术导致强大的再生，使得它们可以在受损的脊柱背柱中再生中央分支。将通过使用 RNA 干扰进行急性基因沉默和辛德比斯病毒过度表达来研究三种转录因子 ATF3、Stat3 和 Smad1 的作用。为了剖析参与介导髓磷脂抑制的分子途径，将通过对分离的神经元以及背根神经节和小脑颗粒细胞的外植体进行髓磷脂抑制测定来研究 p75 和 TROY、NgR1 及其同源物 NgR2 和 NgR3 可能冗余的作用。野生型、p75-/-、TROY-/-、NgR-/- 小鼠或双突变小鼠。 RNA干扰将用于多重敲低。将进行上位性分析以研究p75/NgR受体复合物与表皮生长因子受体(EGFR)之间的通路关系。这种理解可以帮助阐明内在生长状态和外在髓磷脂抑制的机制。