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Reconstruction of the Nigrostriatal pathway

黑质纹状体通路的重建

基本信息

批准号：
8464812
负责人：
George M Smith
金额：
$ 31.65万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464812
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

项目摘要

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.

描述(申请人提供)：使用干细胞或胎儿移植的神经元替代策略是治疗因中枢神经系统(CNS)特定神经回路受损或退化而引起的神经疾病的潜在疗法。帕金森病(PD)就是这样一种疾病，由黑质中的多巴胺能神经元变性引起。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帕金森病的治疗方法，但在大多数情况下，多巴胺能神经元直接移植到它们的目标纹状体，而不是它们的起源部位黑质(SN)。在动物模型和人类帕金森病患者中，这都会导致功能的不完全恢复，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。这一建议将检验一种假设，即在黑质和纹状体之间建立的生长支持通路可以引导移植到帕金森病脑的黑质中的多巴胺能神经元的轴突的生长，从而在解剖学和生理学上正确地重建黑质纹状体通路，并改善帕金森症状。初步数据表明，胶质细胞系衍生神经营养因子(GDNF)及其α-1辅受体(GFR-11)或Netrin-1的结合支持从黑质中的多巴胺能移植到纹状体的长距离轴突生长。在这项研究中，提出了一系列实验，以进一步促进沿路径的生长和纹状体内的靶向。具体目标是：1)单独和联合检测这些和其他潜在的生长因子候选者是否能够支持成人脑内多巴胺能轴突的长距离生长；2)检测BDNF和软骨素酶促进成年纹状体内轴突分支和突触生成的能力；3)使用AIMS 1和2获得的数据重建黑质纹状体路径和检测功能恢复；4)检测多巴胺的释放、细胞类型特异性(A9/A10神经元)和重新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以轴突生长为靶点，使用神经元置换来改善帕金森氏症症状的可行性。这些研究还将为开发其他神经疾病的神经元替代策略提供一个模型。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NT-3 promotes proprioceptive axon regeneration when combined with activation of the mTor intrinsic growth pathway but not with reduction of myelin extrinsic inhibitors.

NT-3与MTOR固有生长途径的激活结合使用时促进本体感受性轴突再生，而不是减少髓磷脂外部抑制剂。

DOI：
10.1016/j.expneurol.2016.05.021
发表时间：
2016-09
期刊：
Experimental neurology
影响因子：
5.3
作者：
Liu Y;Kelamangalath L;Kim H;Han SB;Tang X;Zhai J;Hong JW;Lin S;Son YJ;Smith GM
通讯作者：
Smith GM

Neurotrophin treatment to promote regeneration after traumatic CNS injury.