Axon Guidance Molecules in Nigrostriatal Regeneration

黑质纹状体再生中的轴突引导分子

• 批准号: 6888124
• 负责人: ROBERT E GROSS
• 金额: $ 16.69万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6888124
• 关键词: Parkinson' s disease; axon; central neural pathway /tract; corpus striatum; developmental neurobiology; dopamine; growth cones; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; laser capture microdissection; ligands; messenger RNA; nerve /myelin protein; nervous system regeneration; neural degeneration; neurogenesis; neuronal guidance; neuronal transport; polymerase chain reaction; receptor; substantia nigra

DESCRIPTION (provided by applicant): We are interested in developing strategies for the reconstitution of the dopaminergic (DA) nigrostriatal (NS) pathway that degenerates in Parkinson's disease, an important goal because of the inadequacy of current long-term treatments. Attempts to reconstruct this pathway through transplantation of precursor cells or neurons into the nigra of the adult fail, likely as a result of 1) the presence of inhibitory molecules and/or 2) the absence of trophic and guidance molecules in the adult CNS. Here we propose that an understanding of the molecular events that regulate the development of the nigrostriatal pathway will provide insights for strategies designed to improve NS pathway regeneration in the adult milieu. We propose - and have exciting preliminary data to support - that axon guidance molecules (AGMs), important molecules that direct the development of other projection pathways in the CNS, are expressed in the developing DA NS pathway. A series of experiments are proposed to elucidate the role played by AGMs and their receptors in the development of the NS pathway. Our specific aims are to: 1) Define those AGMs whose receptors are expressed in the developing axons of nigral DA neurons; 2) Define the expression of AGM ligands in relation to the developing NS pathway; 3) For those AGMs that are expressed in an appropriate anatomical relationship to influence NS development, and whose receptors are expressed in developing DA neurons, directly demonstrate chemotropic effects on fetal nigral DA neurons in vitro, and their importance in the development of the NS pathway with blocking studies ex vivo. The outcome of the experiments outlined in this proposal will hopefully be the refinement of means to counteract the inhibitory milieu of the adult injured nervous system, and recapitulate the attractive and repulsive factors that direct axonal outgrowth during development, thereby paving the way for novel reconstructive and regenerative strategies to ameliorate the symptoms of Parkinson's disease. The insights derived from these studies may also have applicability in other neurodegenerative diseases, brain injury and stroke. The research outlined is part of a customized five-year plan of training and career development for the Principal Investigator. The proposal includes active mentoring by experienced scientists, access to diverse resources, and an environment uniquely suited to help the PI develop as an independent neurosurgeon-neuroscientist.

描述（由申请人提供）：我们有兴趣制定策略来重建多巴胺能（DA）nigrostriatal（NS）途径，该途径在帕金森氏病中退化，这是当前长期治疗不足的重要目标。试图通过将前体细胞或神经元移植到成人的NIGRA失败中来重建这一途径，这可能是由于1）存在抑制性分子和/或2）成人CNS中不存在营养和指导分子。在这里，我们建议对调节黑质纹状体途径发展的分子事件的理解将为旨在改善成人环境中NS途径再生的策略提供见解。我们提出的 - 并有令人兴奋的初步数据来支持 - 轴突引导分子（AGM）是指导中枢神经系统中其他投影途径发展的重要分子，在发展中的DA NS途径中表达。提出了一系列实验，以阐明AGM及其受体在NS途径发展中所起的作用。我们的具体目的是：1）定义那些受体在nigral da神经元发展的轴突中表达的AGM； 2）定义与发育中的NS途径相关的AGM配体的表达； 3）对于那些在适当的解剖学关系中表达的AGM，以影响NS发育，其受体在发展DA神经元中表达，直接在体外表现出对胎儿nigral DA神经元的趋化作用，以及它们在NS途径中通过阻止研究的NS途径的重要性。该提案中概述的实验结果有望成为抵制成人受伤神经系统抑制环境的手段，并概括了在发育过程中导致轴突生长的有吸引力和排斥性因素，从而铺平了新的重建性和再生策略，以使新的重建性和再生策略适应parkinson的疾病。从这些研究中得出的见解也可能在其他神经退行性疾病，脑损伤和中风中适用。该研究概述是首席研究人员定制的五年培训和职业发展计划的一部分。该提案包括经验丰富的科学家的积极指导，获得各种资源的机会，以及一个独特的环境，非常适合帮助PI作为独立的神经外科医生 - 神经科学家发展。