Maintenance and Neuroprotection

维护和神经保护

• 批准号: 7382562
• 负责人: Andreas H Kottmann
• 金额: $ 17.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382562
• 关键词: Ablation; Adenoviruses; Adult; Age; Animals; Anxiety; Attention Deficit Disorder; Brain; Cell Survival; Cholinergic Agents; Chronic; Corpus striatum structure; Development; Disease Management; Disease model; Drug Addiction; Erinaceidae; Funding; Genetic; Grant; Growth; Homeostasis; Infection; Intoxication; Kinetics; Lead; Locomotion; Maintenance; Mediating; Mental Depression; Mouse Strains; Mus; Natural regeneration; Neurites; Neurodegenerative Disorders; Neurons; Numbers; Parkinson Disease; Pattern; Principal Investigator; Recombinants; Regulation; Reporter; Schizophrenia; Sonic hedgehog protein; Source; Substantia nigra structure; System; Testing; Tissues; Week; Work; abstracting; cholinergic; design; dopamine system; dopamine transporter; dopaminergic neuron; morphogens; neuroprotection; neuropsychiatry; neurotoxic; novel; novel strategies; pars compacta; programs; recombinase; resilience

Functional and/or structural corruption of the ascending, mesencephalic dopaminergic system is prominent in many neuropsychiatric and neurodegenerative disorders including schizophrenia, Parkinson's disease, attention deficit disorder, drug addiction, depression, and anxiety. A complete understanding of the trophic support mechanisms that lead to the maintenance of the dopamine system in the adult brain might aid in the development of novel strategies for the management of these diseases. Sonic hedgehog, Shh, is expressed in mesencephalic, dopaminergic neurons in the adult mouse brain. Shh, a morphogen, which controls many aspects of ontogeny, orchestrating congruent growth and patterning, also takes part in the regulation of cell survival in many tissues. The genetic ablation of Shh specifically from dopaminergic neurons, which we achieved through the expression of the recombinase Cre controlled by the dopamine transporter (Dat) locus, leads to viable and active animals. However, we observe a progressive deficit in locomotion activity and a reduction of the numbers of both, dopaminergic (DA) neurons in the substantia nigra pars compacta and cholinergic (ChAT) neurons in the striatum, at 12 weeks of age. The objective of this explorative project is to determine whether ablation of shh from dopaminergic neurons (1) leads to a progressive functional and structural corruption of the SNpc and/or striatum in the adult mouse (2) influences the resilience of DA neurons to neurotoxic insults (3) influences the regenerative capacity of DA neurons after neurotoxic insults We expect that work funded through this grant will lead to a novel neurodegenerative disease model. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page Principal Investigator/Program Director (Last, First, Middle):Kottmann, Andreas H. Narrative: Functional and/or structural corruption of the ascending, mesencephalic dopaminergic system is prominent in many neuropsychiatric and neurodegenerative disorders including schizophrenia, Parkinson's disease, attention deficit disorder, drug addiction, depression, and anxiety. The genetic ablation of Shh specifically from dopaminergic neurons, which we achieved through the expression of the recombinase Cre controlled by the dopamine transporter (DAT) locus, leads to a progressive deficit in locomotion activity and a reduction of the numbers of both, dopaminergic (DA) neurons in the substantia nigra pars compacta and cholinergic (ChAT) neurons in the striatum, at 12 weeks of age. Work funded through this grant seeks to determine whether this animal paradigm is a novel neurodegenerative disease model.

在许多神经精神和神经退行性疾病中，包括精神分裂症、帕金森病、注意力缺陷障碍、药物成瘾、抑郁症和焦虑症，中脑多巴胺能系统的上升功能和/或结构损坏是突出的。完整的理解营养支持机制，导致维持多巴胺系统在成年人的大脑可能有助于开发新的战略，这些疾病的管理。Sonic hedgehog，Shh，在成年小鼠脑的中脑多巴胺能神经元中表达。Shh是一种形态发生素，控制个体发育的许多方面，协调一致的生长和模式，也参与许多组织中细胞存活的调节。我们通过多巴胺转运蛋白（Dat）基因座控制的重组酶Cre的表达实现了特异性多巴胺能神经元Shh的基因消融，从而产生了可行的和活跃的动物。然而，我们观察到12周龄时运动活动进行性缺陷，黑质致密部多巴胺（DA）神经元和纹状体胆碱能（ChAT）神经元的数量减少。这个探索性项目的目的是确定从多巴胺能神经元中去除shh（1）是否会导致成年小鼠SNpc和/或纹状体的进行性功能和结构损坏（2）影响DA神经元对神经毒性损伤的恢复力（3）影响神经毒性损伤后DA神经元的再生能力我们希望通过这项资助的工作将导致一种新的神经退行性疾病模型。PHS 398/2590（修订版09/04）第续页格式第页主要研究者/项目负责人（最后，第一，中间）：Kottmann，Andreas H.叙述：在许多神经精神和神经退行性疾病中，包括精神分裂症、帕金森病、注意力缺陷障碍、药物成瘾、抑郁症和焦虑症，中脑多巴胺能系统的上升功能和/或结构损坏是突出的。我们通过表达由多巴胺转运蛋白（DAT）基因座控制的重组酶Cre实现了对多巴胺能神经元特异性Shh的遗传消融，导致运动活动的进行性缺陷和黑质背侧部多巴胺能（DA）神经元和纹状体胆碱能（ChAT）神经元的数量减少，在12周龄时。通过这笔赠款资助的工作旨在确定这种动物范式是否是一种新的神经退行性疾病模型。