Selective Ablation of SOX-2 Expressing Neural Stem Cells

选择性消融表达 SOX-2 的神经干细胞

基本信息

批准号：
7888351
负责人：
Larysa HALYNA Pevny
金额：
$ 22.33万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2006-08-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888351
关键词：
Ablation Address Adult Alleles Animals Astrocytes Biological Assay Brain Cell physiology Cells Cellular Assay Characteristics Cystic Fibrosis Transmembrane Conductance Regulator Data Development Diphtheria Toxin Disease Embryo Embryonic Development Ependymal Cell Funding Generations Generic Drugs Genetic Glial Fibrillary Acidic Protein Growth Health Hematopoietic System In Situ In Vitro Individual Knockout Mice LacZ Genes Location Maintenance Maps Molecular Molecular Profiling Mouse Strains Multipotent Stem Cells Mus Mutagenesis Neural Retina Neuraxis Neuroglia Neurologic Neurons Nucleic Acid Regulatory Sequences Oligodendroglia Phenotype Population Production Prosencephalon Regulatory Element Reporter Research Personnel Retinal Role Signal Pathway Signal Transduction Source Spinal Cord Staging Stem cells Tamoxifen Testing Therapeutic Transgenic Mice adult neurogenesis base in vivo interest nerve stem cell neurogenesis novel progenitor programs prospective recombinase relating to nervous system research study self-renewal stem stem cell population subventricular zone

项目摘要

DESCRIPTION (provided by applicant): Neural stem cells are self-renewing multipotent progenitors that give rise to neurons, astrocytes and oligodendrocytes in the central nervous system (CNS). However, to date it remains unclear whether there exists a generic neural stem cell, as found in the hematopoietic system. It appears that the CNS consists of heterogenic stem cells that, although restricted in their potency, all retain the ability to self-renew, differentiate, and express of a set of universal markers. To understand exactly what characteristics define a neural stem cell it is first necessary to elucidate the lineage relationship between the various types of stem cells and how they contribute to the formation and maintenance of the central nervous system. In this application we propose genetic and cellular assays to determine the contribution of SOX2-expressing cells and function of SOX2 during adult neurogenesis. The experiments are based on our findings that SOX2 universally marks cells with in vitro stem cell potential isolated from all stages of mouse CNS ontogeny (Ellis, 2004; Brazel, 2005). We will take advantage of this neural stem/progenitor specific SOX2 expression to investigate the cellular identity of adult multipotent neural stem cells (NSCs) directly in vivo using genetic lineage tracing and cell-ablation strategies in the mouse. Furthermore, we have recently demonstrated that SOX2 functions to maintain embryonic and retinal neural progenitor identity (Graham, 2003; Taranova, 2005). We therefore hypothesize that the molecular signaling pathway regulated by SOX2 to define neural stem/progenitor identity during embryogenesis also acts to maintain their cellular and molecular profile throughout ontogeny. To address this we propose a conditional mutagenesis approach to test the role of SOX2 specifically in adult neural progenitors. At the end of the funding period we will have a comprehensive view of fate and role of SOX2 expressing cells and the function of the SOX2 signaling cascade in regulating neural stem cell identity and differentiation in the adult CNS. Understanding the origin, fate and function of NSCs will advance efforts to manipulate NSCs for therapeutic purposes.

描述（由申请人提供）：神经干细胞是自我更新的多能祖细胞，会导致中枢神经系统（CNS）中的神经元，星形胶质细胞和少突胶质细胞。但是，迄今为止，尚不清楚造血系统中是否存在通用神经干细胞。 CNS似乎由异质干细胞组成，尽管其效力受到限制，但所有这些都保留了一组通用标记物的自我更新，分化和表达的能力。为了准确了解什么特征定义了神经干细胞，首先需要阐明各种干细胞之间的谱系关系以及它们如何促进中枢神经系统的形成和维持。在此应用中，我们提出遗传和细胞测定法，以确定成人神经发生过程中表达SOX2细胞和SOX2功能的贡献。实验是基于我们的发现，即Sox2普遍标记了从小鼠中枢神经系统个体个体的所有阶段分离出的体外干细胞电位的细胞（Ellis，2004； Brazel，2005）。我们将利用小鼠中的遗传谱系跟踪和细胞燃烧策略来利用这种神经茎/祖细胞特异性SOX2表达在体内研究成年多能神经细胞（NSC）的细胞认同。此外，我们最近证明，Sox2的功能可维持胚胎和视网膜神经祖细胞身份（Graham，2003； Taranova，2005）。因此，我们假设由SOX2调节的分子信号通路在胚胎发生过程中定义神经茎/祖细胞的身份也可以在整个个体发育过程中维持其细胞和分子谱。为了解决这个问题，我们提出了一种有条件的诱变方法，以测试SOX2在成人神经祖细胞中的作用。在资金期结束时，我们将对SOX2表达细胞的命运和作用以及SOX2信号级联的功能进行全面看法，并在调节成人中枢神经系统中的神经干细胞身份和分化中的功能。了解NSC的起源，命运和功能将促进为治疗目的操纵NSC的努力。