Axon Guidance Molecules in Nigrostriatal Regeneration

描述（由申请人提供）：我们有兴趣开发用于重建帕金森病中退化的多巴胺能（DA）黑质纹状体（NS）通路的策略，这是一个重要的目标，因为目前的长期治疗不足。通过将前体细胞或神经元移植到成年人的黑质中来重建该途径的尝试失败，可能是由于1）抑制性分子的存在和/或2）成年人CNS中营养和引导分子的缺乏。在这里，我们建议，了解的分子事件，调节黑质纹状体通路的发展将提供见解的策略，旨在提高NS通路再生在成人环境。我们建议-并有令人兴奋的初步数据支持-轴突导向分子（AGM），重要的分子，直接在中枢神经系统中的其他投射途径的发展，在发展中的DA NS途径表达。提出了一系列的实验来阐明AGM及其受体在NS通路的发展中所发挥的作用。我们的具体目标是：1）确定其受体在黑质DA神经元的发育轴突中表达的那些AGM; 2）确定与发育NS通路相关的AGM配体的表达; 3）对于那些以适当的解剖学关系表达以影响NS发育的AGM，并且其受体在发育中的DA神经元中表达，在体外直接显示对胎儿黑质DA神经元的趋化作用，以及它们在离体阻断研究NS途径的发展中的重要性。本提案中概述的实验结果将有望成为手段的细化，以抵消成年人受伤的神经系统的抑制环境，并概括在发展过程中指导轴突生长的吸引力和排斥力因素，从而为改善帕金森病症状的新的重建和再生策略铺平道路。从这些研究中获得的见解也可能适用于其他神经退行性疾病，脑损伤和中风。概述的研究是为首席研究员定制的培训和职业发展五年计划的一部分。该提案包括经验丰富的科学家的积极指导，获得不同的资源，以及一个独特的环境，以帮助PI发展成为一个独立的神经外科医生-神经科学家。

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.