MECHANISMS OF SPROUTING FOLLOWING NEURAL GRAFTING

神经移植后的发芽机制

• 批准号: 3783003
• 负责人: JOHN T HANSEN
• 金额: --
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3783003
• 关键词: Parkinson's disease; adrenal transplantation; autoradiography; axon; behavior test; brain mapping; cell growth regulation; chromaffin cells; corpus striatum; dihydroxyphenylalanine; disease /disorder model; dopamine receptor; experimental brain lesion; high performance liquid chromatography; histochemistry /cytochemistry; immunocytochemistry; laboratory rat; nervous system regeneration; nervous system transplantation; neurogenesis; neurotrophic factors; nonhuman therapy evaluation; peripheral nervous system; substantia nigra; tegmentum

The principal aim of research into the neurobiology of transplantation has been to develop strategies that would permit the reconstitution of functional capacity in a portion of the nervous system that is damaged. Both fetal mesencephalic grafts and autografts of the adrenal medulla are used experimentally and clinically to address this problem. However, the use of fetal cells has raised ethical questions and the survival of adrenal chromaffin cells is moderate unless neuronotrophic support is provided. Surprisingly, it now is well documented that the host can respond to transplantation, even with poor graft survival, by a sprouting response presumably from spared elements of dopaminergic pathway. Evidence suggests that this host sprouting response may play a very important role in functional recovery in animal models of Parkinson's disease. This proposal will test the hypothesis that a host sprouting response is important for restoring striatal dopamine levels and may be the single most important event in ameliorating functional deficits that result from dopamine depletion in the striatum. This hypothesis will be tested in a selective unilateral 6-OHDA lesioned rat model in which the dopamine neurons of the ventral tegmental area (VTA) are spared but the dopamine neurons of the substantia nigra pars compacta are lesioned. This model more closely resembles the neurodegeneration observed in idiopathic parkinsonism and provides the potential for sprouting from the spared axons of the VTA neurons in response to grafting. The focus of this proposal will be to determine the origin of the sprouting axons, to investigate the mechanisms that initiate the sprouting response, to determine if this response will restore neostriatal dopamine to levels sufficient for functional recovery, and to assess the effects of chronic L-dopa therapy on the host sprouting response. Immunohistochemical, neurochemical, neuroanatomical mapping, receptor autoradiography and behavioral experiments will be employed to address the hypothesis. Long term, we remain convinced that once the basic underlying mechanisms of neural grafting and the host responses are determined, that eventual clinical application will proceed with greater success. In the process, a significant amount of basic neurobiology will be researched with the expected promise of a better understanding of normal and pathological neurology.

移植神经生物学研究的主要目的是 一直在制定战略，允许重组 神经系统受损部分的功能能力。 胎儿中脑移植和自体肾上腺髓质移植都是 在实验和临床上用来解决这个问题。然而， 胎儿细胞的使用引发了伦理问题和肾上腺的生存 嗜铬细胞是中等的，除非提供神经营养支持。 令人惊讶的是，现在很好地记录了宿主可以响应 移植，即使移植物存活率很低，也会产生萌芽反应 可能来自多巴胺能途径的备用元素。有证据表明 这种宿主萌发反应可能在 帕金森氏病动物模型的功能恢复。这项建议 将检验这样一种假设，即宿主萌发反应对 恢复纹状体多巴胺水平可能是最重要的 改善多巴胺引起的功能缺陷的事件 纹状体的耗竭。这一假设将在有选择的 单侧6-OHDA损毁大鼠模型中 腹侧被盖区(VTA)幸免于难，但 黑质致密部损毁。这种模式更贴近 类似于特发性帕金森氏症的神经退行性变 提供了从VTA的备用轴突发芽的可能性 神经元对移植的反应。这项提案的重点将是 确定发芽轴突的来源，以探讨其机制 启动萌芽响应以确定该响应是否 使新纹状体多巴胺恢复到足以恢复功能的水平， 并评价慢性L-多巴疗法对寄主萌发的影响 回应。免疫组织化学，神经化学，神经解剖图谱， 受体放射自显影和行为实验将用于 解决这个假设。从长远来看，我们仍然相信，一旦基本的 神经移植和宿主反应的潜在机制是 下定决心，最终的临床应用将进行更大的 成功。在这个过程中，大量的基础神经生物学将 带着对正常的更好理解的期望进行研究 和病理神经学。