Antagonizing NOS Activity to Induce Neurogenesis in the*

描述（由申请人提供） 一氧化氮（NO）在组织增殖过程中起重要的抗增殖信号作用， 分化与发展。我们最近发现，我们可以抑制NO 产生并导致成体分裂细胞数量的增加 通过将NO合酶（NOS）抑制剂引入脑室来治疗啮齿动物脑。 这种增加在成年人大脑的几个区域都很明显;值得注意的是， 我们在神经发生水平非常低的区域显示了这种效果， 包括皮层和纹状体在本建议中，我们计划研究 将NOS抑制剂引入之前被神经毒剂损伤的大脑 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，其中神经干细胞通过GFP表达标记， 跟踪帕金森病动物模型中移植细胞的命运 疾病，并通过阻断NOS来增加这些细胞的增殖 活动我们进一步提出产生双转基因小鼠系，其中 神经干细胞和分化的多巴胺能神经元将被标记为 两种不同的荧光蛋白的表达。 本建议与《区域财务协定》的目的直接相关， 指南：它提出了一个战略，扭转发病机制 帕金森氏病，并建议开发一种动物模型进行研究 疾病。

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.