EX VIVO ANGIOGENIC GENE TRANSFER IN NEURAL TRANSPLANTS

描述：（逐字地来自申请人的摘要） 帕金森氏病是由特定的退化引起的， 黑质延髓部多巴胺能神经元 中脑相对较新的神经元移植策略， 为帕金森病患者提供了令人鼓舞的结果， 不幸的是，多巴胺能神经元在这些移植物中的存活， 极其贫穷。我们建议增加神经移植中的神经元存活 通过局部刺激血管生成。利用复制缺陷型疱疹 含有人血管内皮生长cDNA的单纯病毒载体 在多巴胺能神经元中，VEGF的表达增加。 胚胎大鼠中脑的培养，并检查是否立体定向 将这些细胞移植到成年大鼠纹状体中， 血管生成和移植物内的神经元存活，例如血管 数量、总细胞数和酪氨酸羟化酶免疫反应阳性细胞数 细胞使用化学损伤的大鼠模型， 多巴胺能缺陷类似于帕金森病，我们将测试 这些移植的有效性和长期生存使用行为测试 例如药物引起的刻板旋转。这些结果的影响 可能会对当前的临床移植策略产生直接影响， 帕金森氏病，而且还具有普遍意义， 在其他神经移植范例中改善细胞存活。

DESCRIPTION: (Verbatim from the Applicant's Abstract) It is well known in humans that Parkinson's disease results from the specific degeneration of dopaminergic neurons in the pars compacta of the substantia nigra of the mesencephalon. The relatively new strategy of neuronal transplantation has provided encouraging results for Parkinson's disease patients, but unfortunately the survival of dopaminergic neurons in these transplants is extremely poor. We propose to increase neuronal survival in neural transplants by focal stimulation of angiogenesis. Using a replication-deficient herpes simplex viral vector containing the cDNA for human vascular endothelial growth factor(VEGF), we propose to increase expression of VEGF in dopaminergic cultures of embryonic rat mesencephalon, and examine whether steriotactic transplantation of these cells into adult rat striatum increases parameters of angiogenesis and neuronal survival within the transplant, such as blood vessel number, total cell number and the number of tyrosine hydroxylase-immunoreactive cells. Using a chemically lesioned rat model which creates a specific dopaminergic deficit similar to that seen in Parkinson's disease, we will test the efficacy and long term survival of these transplants using behavioral tests such as drug-induced stereotypic rotations. The implications of these results could have an immediate impact on current clinical transplantation strategies for Parkinson's disease, and furthermore have general implications for improving cell survival in other neural transplantation paradigms.