Subventricular zone cell migration after injury

损伤后室下区细胞迁移

基本信息

批准号：
7342464
负责人：
FRANCIS G SZELE
金额：
$ 19.7万
依托单位：
UNIVERSITY OF OXFORD
依托单位国家：
美国
项目类别：
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/7342464
关键词：
Adult Animals Antibodies Autologous Brain Brain Hypoxia-Ischemia Brain Injuries CD29 Antigen Cell Nucleus Cells Cerebral cortex Corpus Callosum Corpus striatum structure Data Depth Development Dimensions Disease Electrons Emigrations Environment Goals Grant Green Fluorescent Proteins Hour Image Immigration Immunohistochemistry In Vitro Injury Integrins Intrinsic factor Laminin Lesion Life Light Microscopic Microscopy Modeling Mus Pattern Penetration Phosphorylation Population Preparation Process RNA Interference Research Personnel Role Signal Transduction Signaling Molecule Slice Speed Stem cells Stroke Testing Therapeutic Thinking Time Tissues Toxic effect Transgenic Mice Transplantation Traumatic Brain Injury Video Microscopy brain tissue cell motility design gain of function in vivo laminin-1 loss of function migration mind control nestin protein neuroblast olfactory bulb programs repaired research study stem

项目摘要

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. 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. It is unknown if injury causes changes in intrinsic factors in SVZ cells that are sufficient to drive their emigration. SA 1. Test the hypothesis that intrinsic factors are sufficient to cause SVZ emigration in adult after brain injury. 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 emigrating SVZ cell subpopulations. SA 2. Determine migration patterns of nestin+ and Dcx+ SVZ cells towards injury with mutiphoton 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 and will be determined with RNAi. SA 3. Test the hypothesis that Dcx is necessary for SVZ emigration towards brain injury. Laminin/ alpha6/beta1 integrin signaling is necessary for normal SVZ migration, but whether it is required for their emigration after injury is unknown. SA. 4. Test the hypothesis that Iaminin/a6b1 integrin signaling is necessary for SVZ emigration towards brain injury. 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 candidate molecules that govern different SVZ cell subtype emigration after injury and are predicted to yield information on autologous brain repair in traumatic brain injury and stroke.

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。细胞和环境之间的信号传导如何指示迁移必须是在尝试使用干细胞及其后代进行替代疗法之前要了解这一点。成人脑室下区 (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。 SVZ细胞在几种脑损伤和疾病模型中迁移到相邻的细胞核。在我们所有的具体目标中，我们将使用特征明确的皮质抽吸和缺氧/缺血病变，导致 SVZ 迁移分别朝向大脑皮层和纹状体。目前尚不清楚损伤是否会导致内在的变化 SVZ 细胞中足以驱动其迁移的因素。 SA 1. 检验内在因素的假设足以导致成人脑损伤后 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 nestin-GFP 和 Dcx-GFP 转基因小鼠检查迁移的 SVZ 细胞亚群。 SA 2.确定nestin+和Dcx+SVZ的迁移模式多光子视频显微镜对细胞造成损伤。尽管 DCx 调节哺乳动物皮质发育并由迁移的 SVZ 神经母细胞特异性表达，是否是 SVZ 所必需的迁移和迁移是未知的，将通过 RNAi 来确定。 SA 3. 检验假设 Dcx 是 SVZ 迁移至脑损伤所必需的。层粘连蛋白/α6/β1整合素信号传导对于 SVZ 正常迁移，但受伤后是否需要迁移尚不清楚。 SA。 4. 测试假设层粘连蛋白/a6b1 整合素信号传导对于 SVZ 迁移至脑损伤是必需的。这具体目标旨在相互补充并具有内在重要性。他们将进一步推动我们的了解一般规则以及控制不同 SVZ 细胞亚型的候选分子受伤后迁移，预计会产生有关创伤性脑部自体脑修复的信息受伤和中风。