Angiogenic Enhancement of Dopamine Neuron Grafts

描述（由申请人提供） 通过移植纹状体多巴胺（DA）水平的策略 DA产生细胞对帕金森病的治疗有很大的希望 （PD）。临床成功的关键是开发方法， 移植的DA神经元存活率和宿主纹状体的神经再支配显著降低， 增加这一目标适用于初级中脑组织， 移植物以及替代组织来源，例如茎-和 祖细胞衍生的DA神经元。胎儿多巴胺能神经元存活率的研究 年轻成年大鼠的中脑移植物为5- 10%。我们的实验室最近 结果表明，移植到老年纹状体的存活率更低。 我们的研究表明，大量的凋亡细胞死亡发生在 在移植后的头几天内移植，然后急剧 减少。毫不奇怪，这一时间进程与 移植细胞的宿主血管化。缺乏血液营养， 包括氧气，移植细胞在移植后即刻 移植后间隔是触发细胞凋亡的可能候选者。整体 该提议的假设是，移植的DA神经元存活严重 由于移植后早期缺乏血液营养， 当移植的细胞没有充分血管化时的间隔。因此 转血管内皮细胞基因促进移植物血管化 生长因子（VEGF）将显著增加移植物的活力， 宿主纹状体的神经再支配该策略将使用 初级中脑组织然而，这些研究的结果将 适用于DA神经元的替代来源，包括干细胞和 祖细胞衍生的细胞。

DESCRIPTION (provided by applicant) The strategy of augmenting striatal dopamine (DA) levels via grafts of DA-producing cells holds great promise for the treatment of Parkinson's disease (PD). Critical to clinical success is the development of methods whereby grafted DA neuron viability and reinnervation of the host striatum are markedly increased. This objective holds true for both primary mesencephalic tissue grafts as well as for alternative tissue sources such as stem- and progenitor-derived DA neurons. The survival rate of DA neurons in fetal mesencephalic grafts to young adult rats is 5-10%. Our laboratory has recently demonstrated that this survival is even poorer in grafts to the aged striatum. Our research indicates that massive apoptotic cell death occurs within the graft during the first few days after transplantation and then sharply diminishes. Not surprisingly, this timecourse closely parallels the delay in host vascularization of the grafted cells. The lack of blood-borne nutrients, including oxygen, experienced by the grafted cells during the immediate post-grafting interval is a likely candidate to trigger apoptosis. The overall hypothesis of this proposal is that grafted DA neuron survival is severely limited by lack of blood-borne nutrients during the early post-transplantation interval when grafted cells are not adequately vascularized. Therefore augmentation of graft vascularization via gene transfer of vascular endothelial growth factor (VEGF) will significantly augment graft viability and subsequent reinnervation of the host striaturn. This strategy will be evaluated using primary mesencephalic tissue. However, results from these studies will be applicable to alternative sources of DA neurons, including stem- and progenitor-derived cells.