Reconstruction of the Nigrostriatal pathway

黑质纹状体通路的重建

• 批准号: 8448738
• 负责人: George M Smith
• 金额: $ 32.8万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448738
• 关键词: Address; Adult; Adverse effects; Animal Model; Axon; Behavior; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Cells; Cessation of life; Cholera Toxin; Chondroitin Sulfate Proteoglycan; Chondroitinases; Clinic; Clinical Trials; Contralateral; Corpus Callosum; Corpus striatum structure; Data; Dendritic Spines; Disease; Dopamine; Electron Microscopy; Embryo; Ensure; FGF2 gene; Functional disorder; Growth; Growth Factor; Health; Human; Hyaluronidase; Image; Injection of therapeutic agent; Label; Laboratories; Left; Maps; Measures; Microelectrodes; Modeling; Motor; Neuraxis; Neurodegenerative Disorders; Neurons; Outcome Study; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pharmaceutical Preparations; Probability; Rattus; Recombinants; Recovery of Function; Replacement Therapy; Research Personnel; Series; Site; Source; Specificity; Stem cells; Subfamily lentivirinae; Substantia nigra structure; Symptoms; Synapses; Time; Transplantation; axon growth; cell type; density; dopaminergic neuron; fetal; functional restoration; glial cell-line derived neurotrophic factor; human NTN1 protein; improved; in vivo; motor deficit; nervous system disorder; netrin-1; neural circuit; neuronal cell body; neuronal replacement; nigrostriatal pathway; overexpression; receptor; reconstruction; relating to nervous system; research study; restoration; synaptogenesis

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.

描述（由申请人提供）：使用干细胞或胎儿移植的神经元替代策略是因中枢神经系统（CNS）损害或特定神经回路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，是由黑质尼格拉植物多巴胺能神经元变性引起的。在实验室和诊所中，许多研究者已经探索了神经移植作为PD的治疗，但是在大多数情况下，多巴胺能神经元直接移植到其靶标 - 纹状体 - 而不是将其起源部位（SN）移植到其起源部位。这会导致动物模型和人类PD患者的功能恢复不完全，因为移植神经元为纹状体提供了多巴胺来源，但不会重新建立退化的神经回路。该提议应研究以下假设：SN和纹状体之间创建的具有生长的途径可以指导从多巴胺能神经元移植到帕金森氏症大脑SN中的轴突的生长，从而在解剖和生理上正确地在生理上正确地重新建立了北美triatiatriatal Pathway和parkinsonianian的Amelierianian somemitation and nigriatiriatal Pathway和Amelierian somemanian症状。提出了初步数据，表明神经胶质细胞系的神经营养因子（GDNF）及其α-1CO受体（GFR-111）或Netrin-1支持长距离轴突从SN中的多巴胺能移植物中的长距离轴突生长到纹状体。在这项研究中，提出了一系列实验，以进一步增强沿途径并靶向纹状体内的生长。具体目的是：1）单独检查这些和其他潜在的生长因子候选物，并结合起来支持成人大脑中多巴胺能轴突长距离生长的能力； 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AIM 1和2获得的数据重建黑质纹状体途径并检查功能恢复； 4）检查多巴胺，细胞类型特异性（A9/A10神经元）的释放，以及重新发明纹状体的多巴胺能轴突的突触连通性。这些研究的结果将证明使用神经元替代靶向轴突生长以减轻帕金森氏病的症状的可行性。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。公共卫生相关性帕金森氏病是一种广泛的神经退行性疾病，表现出严重的运动功能障碍最终导致死亡。当前的细胞替代疗法和药物治疗在临床试验中已经失败，或者会诱导长期副作用和随着时间的推移效力丧失。重建损伤电路的神经元替代策略具有降低或逆转与帕金森氏病以及许多其他神经系统疾病相关的运动缺陷的可能性。