Subventricular Zone Responses to Neonatal Hypoxia-Ischemia

室下区对新生儿缺氧缺血的反应

基本信息

批准号：
7162917
负责人：
MARIA LUZ VALDECANAS DIZON
金额：
$ 14.53万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
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：
2006-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7162917
关键词：
Adult Affect Area Basic Science Behavior Biological Assay Brain Brain Hypoxia-Ischemia Brain Injuries Bromodeoxyuridine Cell Nucleus Cells Cerebral Palsy Corpus striatum structure DNA Development Developmental Disabilities Embryo Emigrations Environment Goals Green Fluorescent Proteins Immigration Immunohistochemistry Impaired cognition In Vitro Infant Infection Injury Intrinsic factor Investigation Ischemic-Hypoxic Encephalopathy Label Lentivirus Vector Lesion Libraries Lifting Mentors Microscopy Middle Cerebral Artery Occlusion Molecular Morphology Mus Neonatal Neonatology Neurodevelopmental Disability Neuroglia Neurology Neurons Newborn Infant Numbers Occlusion injury Oligodendroglia Pediatrics Phenotype Polymerase Chain Reaction Positioning Attribute Process Prosencephalon Protein Overexpression RNA Interference Rattus Relative (related person)Research Personnel Resources Retroviridae Rice Score Signal Transduction Slice Source Stream Testing Time Tissues Universities Week Wild Type Mouse artery occlusion career cell behavior cell motility in vivo in vivo Model injured ischemic lesion lateral ventricle mature animal medical schools middle cerebral artery migration mouse model movie neonatal hypoxic-ischemic brain injury neonate nerve stem cell neuroblast olfactory bulb oligodendrocyte precursor postnatal professor programs repaired response small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Hypoxic-ischemic brain injury affects 150,000 infants per year, resulting in developmental disabilities including cognitive impairment and cerebral palsy. Though no therapies exist, cell replacement from the subventricular zone (SVZ), a source of neural stem cells (NSCs), holds exciting promise. In development, neuroblasts from the SVZ migrate to the olfactory bulbs and a separate lineage of glioblasts migrates throughout the forebrain. After middle cerebral artery occlusion in adult rats SVZ cells move toward the ischemic lesion, but their migratory response to neonatal hypoxia-ischemia (H/l) has not been defined. This proposal will examine the SVZ's response to H/l, specifically whether SVZ neuroblasts become redirected toward the lesion, whether SVZ glioblasts move into the forebrain in greater numbers, and whether SVZ cell fate becomes shifted towards neurons. Processes of neural cell migration and differentiation are inextricably tied; differentiated phenotypes emerge as migration ceases. While the neuroblast marker Doublecortin (Dcx) is necessary for embryonic cortical migration, it is unknown whether it is necessary for migration towards neonatal H/l lesions. The candidate proposes to test the following hypotheses in 3 Aims: 1) that SVZ neuroblasts and glioblasts redirect their migration toward brain areas injured by H/l; 2) that SVZ NSCs expand lineage restrictions following H/l; and 3) that Dcx is necessary for SVZ neuronal migration in response to H/l. She will employ the Rice-Vannucci model of in vivo H/l, neurosphere and slice cultures, retroviral tagging and lineage analysis, multiphoton time-lapse microscopy and RNA interference. Investigations will provide an important understanding of SVZ cell behavior in response to neonatal H/l and serve as a starting point for developing strategies to harness endogenous NSCs for repair. Furthermore, they will define the lineage relationships between SVZ neurons and glia. The candidate's long-term career goal is to develop an academic career in Neonatology with a basic research focus on neural stem cell responses to hypoxia-ischemia. The rich environment provided by her mentor Dr. Francis Szele, Assistant Professor of Pediatrics, by her co-mentor Dr. John Kessler, Professor and Chair of Neurology, and by Northwestern University Feinberg School of Medicine will provide the resources necessary to help her to achieve her objectives.

描述（由申请人提供）：缺氧 - 缺血性脑损伤每年影响15万名婴儿，导致发育障碍，包括认知障碍和脑瘫。尽管不存在疗法，但神经干细胞（NSCS）的室内区（SVZ）的细胞替换具有令人兴奋的前景。在开发中，从SVZ的神经细胞迁移到嗅球，而单独的胶质细胞谱系在整个前脑中迁移。在成年大鼠SVZ细胞中脑动脉阻塞后，尚未定义它们对新生儿缺氧 - 缺血（H/L）的迁移反应。该提案将检查SVZ对H/L的反应，特别是SVZ神经细胞是否重定向到病变，SVZ胶质细胞是否以更大的数量进入前脑，以及SVZ细胞命运是否转向神经元。神经细胞迁移和分化的过程密不可分。分化的表型随着迁移的停止而出现。虽然神经细胞标记doublecortin（DCX）对于胚胎皮质迁移是必需的，但尚不清楚是否需要向新生儿H/L病变迁移。候选人提议在3个目标中检验以下假设：1）SVZ神经细胞和胶质细胞将其迁移重定向到由H/L受伤的大脑区域的迁移； 2）SVZ NSC在H/L之后扩大了谱系限制； 3）DCX对于响应H/L的SVZ神经元迁移是必需的。她将采用体内H/L，神经圈和切片培养物，逆转录病毒标记和谱系分析，多光子延时显微镜和RNA干扰的水稻vannucci模型。调查将对新生儿H/L响应SVZ细胞行为有一个重要的理解，并作为制定策略来利用内源性NSC进行修复的起点。此外，它们将定义SVZ神经元与神经胶质之间的谱系关系。候选人的长期职业目标是发展新生儿学的学术职业，基础研究重点是神经干细胞对缺氧 - 疾病的反应。她的导师弗朗西斯·塞尔（Francis Szele）博士，儿科助理教授提供的丰富环境，由她的同事约翰·凯斯勒（John Kessler）博士，神经病学教授兼主席约翰·凯斯勒（John Kessler），西北大学费恩伯格医学院（Feinberg University Feinberg University of Feinberg School of Medicine）提供的资源将提供必要的资源来帮助她实现自己的目标。