Subventricular zone cell migration after injury

损伤后室下区细胞迁移

• 批准号: 7050289
• 负责人: FRANCIS G SZELE
• 金额: $ 32.34万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050289
• 关键词: RNA interference; astrocytes; biological signal transduction; blocking antibody; brain injury; cell migration; cerebral ischemia /hypoxia; cerebral ventricles; corpus callosums; experimental brain lesion; genetically modified animals; green fluorescent proteins; immunoelectron microscopy; integrins; intermolecular interaction; laboratory mouse; laminin; monoclonal antibody; nerve stem cell; receptor expression; sectioning; stem cell transplantation; transfection /expression vector; video microscopy

DESCRIPTION (provided by applicant): Interactions between cells and the environment are essential for stimulating normal migration and inhibiting aberrant migration. How the signaling between cells and the environment instructs migration must be understood before attempting to use stem cells and their progeny for replacement therapeutics. The adult brain subventricular zone (SVZ) contains nestin-positive stem and progenitor cells that give rise to doublecortin (Dcx)-positive neuroblasts, which in turn migrate long-distances to the olfactory bulbs. SVZ cells emigrate to adjacent nuclei in several models of brain injury and disease. The relative control of SVZ migration by intrinsic versus environmental signals is unknown. In all of our specific aims, we will use well characterized cortical aspiration and hypoxia/ischemia lesions, which cause SVZ emigration towards the cerebral cortex and the striatum, respectively. S.A. 1. Test the hypothesis that both intrinsic and environmental signals cause SVZ emigration in adult after brain injury with cross-transplantation. We have evidence that nestin-positive SVZ cells also migrate in the adult SVZ, therefore we will compare nestin-GFP and Dcx-GFP transgenic mice to examine migrating SVZ cell subpopulations. S.A. 2. Determine migration patterns of nestin+ and Dcx+ SVZ cells towards injury with multiphoton videomicroscopy. Though Dcx regulates mammalian cortical development and is specifically expressed by migrating SVZ neuroblasts, whether it is necessary for SVZ migration and emigration is unknown. S.A. 3. Test the hypothesis that Dcx is necessary for emigration of SVZ cells towards brain injury by knocking it down with RNAi. The specific aims are designed to be complementary and to also have intrinsic importance. They will further our understanding of general rules as well as of a candidate gene that governs different SVZ cell subtype migration and are predicted to yield information on autologous brain repair in traumatic brain injury and stroke.

描述（由申请人提供）：细胞与环境之间的相互作用对于刺激正常迁移和抑制异常迁移至关重要。在尝试使用干细胞及其后代进行替代疗法之前，必须了解细胞和环境之间的信号传导如何指导迁移。成人大脑室下区 (SVZ) 含有巢蛋白阳性干细胞和祖细胞，可产生双皮质素 (Dcx) 阳性神经母细胞，进而长距离迁移至嗅球。在几种脑损伤和疾病模型中，SVZ 细胞迁移到邻近的细胞核。内在信号与环境信号对 SVZ 迁移的相对控制尚不清楚。在我们所有的具体目标中，我们将使用特征明确的皮质吸入和缺氧/缺血病变，这分别导致 SVZ 向大脑皮层和纹状体迁移。 S.A. 1. 检验以下假设：内在信号和环境信号均导致成人交叉移植脑损伤后 SVZ 移出。我们有证据表明巢蛋白阳性 SVZ 细胞也在成年 SVZ 中迁移，因此我们将比较巢蛋白-GFP 和 Dcx-GFP 转基因小鼠以检查迁移的 SVZ 细胞亚群。 S.A. 2. 使用多光子视频显微镜确定巢蛋白 + 和 Dcx+ SVZ 细胞向损伤的迁移模式。尽管 Dcx 调节哺乳动物皮质发育，并且由迁移的 SVZ 神经母细胞特异性表达，但它对于 SVZ 迁移和移出是否是必需的尚不清楚。 S.A. 3. 通过用 RNAi 将 SVZ 细胞击倒来检验 Dcx 对于 SVZ 细胞迁移至脑损伤所必需的假设。具体目标旨在互补且具有内在重要性。它们将进一步加深我们对一般规则以及控制不同 SVZ 细胞亚型迁移的候选基因的理解，并预计将产生有关创伤性脑损伤和中风的自体大脑修复的信息。