EX VIVO ANGIOGENIC GENE TRANSFER IN NEURAL TRANSPLANTS

描述：(一字不差地摘自申请者的摘要)这是众所周知的 人类认为帕金森氏症是由特定的退行性变引起的 大鼠黑质致密部的多巴胺能神经元 中脑。相对较新的神经元移植策略已经 为帕金森氏症患者提供了令人鼓舞的结果，但 不幸的是，多巴胺能神经元在这些移植中的存活 非常穷。我们建议提高神经移植中神经元的存活率。 通过局部刺激血管生成。使用复制缺陷疱疹 人血管内皮细胞生长的单纯病毒载体 因子(VEGF)，我们建议增加多巴胺能神经元中VEGF的表达。 胚胎大鼠中脑的培养，并检测是否具有无菌作用 将这些细胞移植到成年大鼠纹状体增加了参数 移植血管内的血管生成和神经元存活 酪氨酸羟基酶免疫反应阳性细胞数、细胞总数和数量 细胞。使用一种化学损伤的大鼠模型，这种模型可以产生特定的 与帕金森氏症类似的多巴胺能缺陷，我们将测试 用行为学测试评估这些移植的有效性和长期存活率 比如药物引起的刻板印象旋转。这些结果的含义 可能会对当前的临床移植策略产生直接影响 帕金森氏症，并进一步对 在其他神经移植范例中提高细胞存活率。

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.