Evaluation of Hypoxia in Grafted Dopamine Neurons

描述（由申请人提供）：神经系统疾病的脑内神经移植策略受到移植细胞存活率低的限制。例如，在帕金森病动物模型和帕金森病患者的临床试验中移植的多巴胺（DA）神经元的存活率仅为5- 20%。临床成功的关键是开发移植的DA神经元活力和宿主纹状体的神经再支配显着增加的方法。本R 03应用的重点是直接检查缺氧的作用，在脑内移植利用一个良好的范例，移植中脑DA神经元。我们的研究表明，移植中脑细胞的大量凋亡发生在移植后的最初几天内，然后急剧减少。移植DA神经元死亡的时间过程与移植细胞的宿主血管化延迟密切相关。在移植后立即间隔期间，移植细胞经历的血源性氧的缺乏或缺氧是触发凋亡性细胞死亡的可能候选者。然而，缺氧在限制移植物存活中的作用从未被直接评估。这个建议的总体假设是，移植的DA神经元的生存是严重限制了缺氧移植后的早期间隔时，移植的细胞没有充分血管化。缺氧作为移植物存活的一个重要限制因素的鉴定将指导未来的策略，旨在增强植入的多种细胞类型（原代细胞，干细胞）的脑内移植物，以治疗广泛的神经系统疾病。

DESCRIPTION (provided by applicant): Intracerebral neural grafting strategies for neurological disorders are limited by the poor survival rate of grafted cells. For example, the survival rate of dopamine (DA) neurons grafted in parkinsonian animal models and in clinical trials with Parkinson s patients is merely 5-20%. Critical to clinical success is the development of methods whereby grafted DA neuron viability and reinnervation of the host striatum are markedly increased. The focus of this R03 application is to directly examine the role of hypoxia in intracerebral grafts utilizing a well-established paradigm, grafts of mesencephalic DA neurons. Our research indicates that massive apoptosis of grafted mesencephalic cells occurs within the first few days after transplantation and then sharply diminishes. This time course of grafted DA neuron death closely parallels the delay in host vascularization of the grafted cells. The lack of blood-borne oxygen, or hypoxia, experienced by the grafted cells during the immediate post-grafting interval is a likely candidate to trigger apoptotic cell death. However, the role of hypoxia in limiting graft survival has never been directly assessed. The overall hypothesis of this proposal is that grafted DA neuron survival is severely limited by hypoxia during the early post-transplantation interval when grafted cells are not adequately vascularized. Identification of hypoxia as a significant constraint on graft survival would direct future strategies aimed at enhancing intracerebral grafts of numerous cell types (primary cells, stem cells) implanted to treat a wide range of neurological disorders.