Antagonizing NOS Activity to Induce Neurogenesis in the*

描述(由申请人提供) 一氧化氮(NO)在组织中起着重要的抗增殖信号作用 差异化发展。我们最近发现，我们可以抑制NO 并导致成虫分裂细胞数量的增加 通过将一氧化氮合酶(NOS)抑制剂引入到脑室来研究啮齿类动物的大脑。 这种增加在成人大脑的几个区域很明显；显著的是， 我们在神经发生水平非常低的区域显示了这种效应， 包括大脑皮层和纹状体。在这项提案中，我们计划研究 将一氧化氮合酶抑制剂引入先前由神经毒性药物损害的大脑 可诱导黑质纹状体神经元增殖。我们还建议使用 转基因小鼠品系，其中神经干细胞以GFP表达为标记， 在帕金森病动物模型中观察移植细胞的命运 通过阻断一氧化氮合酶来促进这些细胞的增殖 活动。我们进一步建议创造一个双转基因小鼠系，其中 神经干细胞和分化的多巴胺能神经元将通过 表达两种不同的荧光蛋白。 这项建议直接关系到本RFA的目的，如 指南：它提出了一种逆转糖尿病发病机制的策略 帕金森氏症，并建议开发一种动物模型进行研究 这种疾病的危害。

DESCRIPTION (provided by applicant) Nitric oxide (NO) acts as an essential antiproliferative signal during tissue differentiation and development. We have recently found that we can inhibit NO production and cause an increase in the number of dividing cells in the adult rodent brain by introducing NO synthase (NOS) inhibitors into brain ventricles. This increase was evident in several areas of the adult brain; significantly, we showed this effect in the areas which have very low levels of neurogenesis, including the cortex and striatum. In this proposal we plan to examine whether introducing NOS inhibitors into brains previously lesioned by neurotoxic agents can induce proliferation of nigrostriatal neurons. We also propose to use a line of transgenic mice, where neural stem cells are marked by GFP expression, to follow the fate of transplanted cells in animal models of Parkinson's disease, and to augment the proliferation of these cells by blocking NOS activity. We further propose to generate a double-transgenic mouse line where neural stem cells and differentiated dopaminergic neurons will be marked by the expression of two different fluorescent proteins. This proposal directly relates to the purpose of this RFA as stated in the guidelines: it proposes a strategy for reversing the pathogenesis of Parkinson's disease and it proposes developing an animal model for the studies of the disease.