Reconstruction of the Nigrostriatal pathway

描述（由申请人提供）：使用干细胞或胎儿移植的神经元置换策略是治疗中枢神经系统（CNS）中特定神经回路损伤或变性引起的神经系统疾病的潜在治疗方法。帕金森氏病（PD）是一种这样的疾病，由黑质中的多巴胺能神经元的变性引起。许多研究人员已经在实验室和临床上探索了神经移植作为PD的治疗方法，但在大多数情况下，多巴胺能神经元直接移植到它们的靶点-纹状体-而不是它们的起源部位-黑质（SN）。这导致动物模型和人类PD患者的功能恢复不完全，因为移植的神经元为纹状体提供了多巴胺来源，但不能重建退化的神经回路。该提案将检验这样的假设：SN和纹状体之间创建的生长支持途径可以引导移植到帕金森病大脑SN的多巴胺能神经元轴突的生长，从而在解剖学和生理学上正确地重建黑质纹状体途径并改善帕金森病症状。初步数据显示，胶质细胞系源性神经营养因子（GDNF）及其α-1受体（GFR-11）或netrin-1的组合支持从SN中的多巴胺能移植物到纹状体的长距离轴突生长。在本研究中，提出了一系列的实验，以进一步增强生长沿着通路和靶向内纹状体。具体目标是：1）单独地和组合地检查这些和其它潜在的生长因子候选物支持多巴胺能轴突在成年脑内长距离生长的能力; 2）检查BDNF和软骨素酶增强成年纹状体内轴突分支和突触发生的能力; 3）使用从目的1和2获得的数据重建黑质纹状体通路并检查功能恢复; 4）检查多巴胺的释放、细胞类型特异性（A9/A10神经元）和重新神经支配纹状体的多巴胺能轴突的突触连接。这些研究的结果将证明使用神经元替代来靶向轴突生长以改善帕金森病症状的可行性。这些研究还将为开发其他神经系统疾病的神经元替代策略提供模型。帕金森病是一种广泛的神经退行性疾病，表现为严重的运动功能障碍，最终导致死亡。目前的细胞替代疗法和药物治疗要么在临床试验中失败，要么随着时间的推移引起长期副作用和功效丧失。重建损伤回路的神经元置换策略很有可能减少或逆转与帕金森病以及许多其他神经系统疾病相关的运动缺陷。

DESCRIPTION (provided by applicant): Neuronal replacement strategies using stem cells or fetal transplants are potential treatments for neurological disorders caused by damage or degeneration of specific neural circuits in the central nervous system (CNS). Parkinson's disease (PD) is one such disorder, caused by the degeneration of dopaminergic neurons in the substantia nigra. Many investigators have already explored neural transplantation as therapy for PD, both in the lab and in the clinic, but in most cases, dopaminergic neurons are transplanted directly into their target - the striatum - rather than into their site of origin, the substantia nigra (SN). This leads to incomplete recovery of function both in animal models and in human PD patients, because the transplanted neurons provide a dopamine source to the striatum but do not reestablish the degenerated neural circuit. This proposal shall examine the hypothesis that a growth-supportive pathway created between the SN and the striatum can guide the growth of axons from dopaminergic neurons transplanted into the SN of the parkinsonian brain, resulting in an anatomically and physiologically correct reestablishment of the nigrostriatal pathway and an amelioration of parkinsonian symptoms. Preliminary data is presented showing that a combination of glial cell line-derived neurotrophic factor (GDNF) and its alpha-1co-receptor (GFR-11) or netrin-1 support long distance axon growth from dopaminergic transplants in the SN to the striatum. In this study, a series of experiments are proposed to further enhance the growth along the pathway and targeting within the striatum. The specific aims are to: 1) examine these and other potential growth factor candidates either individually and in combination for their ability to support long distance growth of dopaminergic axons within the adult brain; 2) examine the ability BDNF and chondroitinase to enhance axon branching and synaptogenesis within the adult striatum; 3) reconstruct the nigrostriatal pathway using data acquired from Aims 1 and 2 and examine functional recovery; 4) examine the release of dopamine, cell type specificity (A9/A10 neurons), and synaptic connectivity of dopaminergic axons re-innervating the striatum. The outcome of these studies will demonstrate the feasibility of targeting the growth of axons using neuronal replacement to ameliorate the symptoms of Parkinson's disease. These studies will also provide a model for developing neuronal replacement strategies for other neurological disorders. PUBLIC HEALTH RELEVANCE Parkinson's disease is a widespread neurodegenerative disease that manifests severe motor dysfunction ultimately leading to death. Present cell replacement therapies and drug treatments have either failed in clinical trials or induce long term side effect and loss of efficacy over time. Neuronal replacement strategies that rebuild the damage circuit have a high probability of reducing or reversing motor deficits associated with Parkinson's disease as well as numerous other neurological disorders.