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敌对环境以及成熟神经元的仪器再生能力的降低。背根神经神经元的外围分支的轴切开术会导致强大的再生，从而可以在病变的脊柱背柱中再生其中心分支。通过将RNA干扰用于急性基因分解和Sindbis病毒以进行过表达，将研究三个转录因子ATF3，STAT3和SMAD1的作用。为了解剖介导髓磷脂抑制所涉及的分子途径，将研究p75和Troy，Ngr1及其同源物NGR2和NGR3的冗余作用，通过对两种骨神经元和脑神经蛋白神经元的分离神经元和外层进行分离的神经元和外层的骨髓素抑制测定，研究。 NGR - / - 小鼠或双突变小鼠。 RNA干扰将用于多次敲低。上位分析将进行研究以研究p75/NGR受体复合物与表皮生长因子受体（EGFR）之间的途径关系。这种理解可以帮助阐明内在生长状态和外部髓鞘抑制的机制。