FUNCTION OF CNS NEURAL GRAFTS

中枢神经系统神经移植物的功能

• 批准号: 6112032
• 负责人: BARRY J. HOFFER
• 金额: $ 12.74万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112032
• 关键词: 6 hydroxydopamine; aging; basal ganglia; corpus striatum; dopamine; dopamine agonists; electron microscopy; embryo /fetus cell /tissue; experimental brain lesion; glia; homologous transplantation; human fetus tissue; immunocytochemistry; laboratory mouse; laboratory rat; methylphenyltetrahydropyridine; nervous system transplantation; neurogenesis; neurons; neurotoxins; neurotrophic factors; substantia nigra; transforming growth factors; transplantation immunology; xenotransplantation

This project will examine the in vivo actions of a newly described putative dopaminotrophic (DA) factor, glial cell-derived neurotrophic factor (GDNF) in rats. The proposal will test the hypotheses that GDNF is a specific trophic factor for developing and mature midbrain DA neurons, that GDNF will support human as well as rat DA circuits, and that GDNF will counteract the deleterious effects of dopaminergic neurotoxins. It is proposed to examine actions of GDNF on dopaminergic pathways in situ in rats and mice. Interactions of GDNF with dopaminergic neurotoxins, such as 6-OHDA (rats) and MPTP (mice) will be evaluated both with "protection' and with facilitation of regeneration protocols. Target appropriateness will be evaluated in situ. GDNF will be studied in mature and immature syngeneic and allogeneic intracranial grafts and in immature human xenografts to aid further insight into the utility of this molecule to augment growth, differentiation, maintenance, and survival of DA neurons. This proposal will also examine GDNF effects on DA circuitry in aged non- lesioned rats, to test hypothesis about reversal of senescence-induced dopaminergic dysfunction. Finally, a second TGF-beta family molecule, OP-1 will be evaluated for dopaminotrophic activity int eh 6-OHDA lesion model. Actions of GDNF will be evaluated using behavioral, histochemical and in vivo electrochemical techniques. Neurochemical and electrophysiological protocols will also be utilized. Markers for apoptosis will be utilized to differentiate between survival-promoting and proliferative actions of GDNF on DA neurons. Project 3 will also provide lesioned/transplanted animals and behavioral/electrophysiological/histochemical evaluations for many of the other projects in this center.

这个项目将研究一种新描述的推定的在体内的行为 多巴胺营养因子、胶质细胞源性神经营养因子 在老鼠身上。该提案将检验GDNF是一种特定的 中脑DA神经元发育和成熟的营养因子，即GDNF 将支持人类和大鼠DA电路，GDNF将 中和多巴胺能神经毒素的有害作用。它是 建议研究GDNF在原位多巴胺能通路中的作用 老鼠和老鼠。神经营养因子与多巴胺能神经毒素的相互作用 6-OHDA(大鼠)和MPTP(小鼠)将被评价为“保护”和 在再生方案的促进下。目标适当性将 在现场进行评估。GDNF将在成熟和未成熟两种情况下进行研究 同基因和同种异体颅内移植物及未成熟人 异种移植，以帮助进一步了解这种分子在 促进DA神经元的生长、分化、维持和存活。 这项建议还将研究GDNF对老年非老年患者DA回路的影响 损毁大鼠，验证逆转衰老的假说 多巴胺能功能障碍。最后，第二个转化生长因子-β家族分子OP-1 将在6-OHDA损伤模型中评估多巴胺营养活性。 GDNF的作用将通过行为、组织化学和 活体电化学技术。神经化学和电生理学 还将利用协议。将利用细胞凋亡的标志物 胶质细胞源性神经营养因子促存活和促增殖作用的鉴别 在多巴胺神经元上。项目3还将提供受损/移植的动物。 以及行为/电生理/组织化学评估 这个中心的其他项目。