Molecular control of neurogenesis in the adult subventricular zone

成人室下区神经发生的分子控制

• 批准号: 8883856
• 负责人: KENNETH J CAMPBELL
• 金额: $ 48.26万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883856
• 关键词: Adult; Amphibia; BHLH Protein; Biological Models; Brain; Brain Injuries; Cells; ChIP-seq; Chromatin Remodeling Factor; Complex; Data; Development; Ectopic Expression; Embryo; Erinaceidae; Evolution; Exhibits; Fishes; Future; Gene Expression Profile; Generations; Genes; Genetic; Genetic Epistasis; Goals; Health; Human; Injury; Interneurons; Knowledge; Light; Modeling; Molecular; Mus; Natural regeneration; Neuroglia; Neurons; Outcome Study; Play; Polycomb; Regulation; Research; Role; Signal Pathway; Social Welfare; Staging; System; Testing; Up-Regulation; adult neurogenesis; base; brain repair; clinical application; gain of function; genome-wide; homeodomain; in vivo; injured; insight; loss of function; nerve stem cell; neural circuit; neuroblast; neurogenesis; novel; olfactory bulb; progenitor; public health relevance; regenerative; repaired; subventricular zone; tool; transcription factor

 DESCRIPTION (provided by applicant): Neural stem cells (NSCs) in the adult mammalian brain have been demonstrated to play important roles in the plasticity of higher brain function and repair and regeneration after brain damage. Yet, our understanding of the regulation of adult NSCs at the molecular level remains sketchy, and this is one of the reasons for why strategies to harness the capacity of endogenous NSCs for brain repair have not yet made sufficient progress for clinical applications. The goal of this study is to fill in this current knowledge gap by identifying crucial regulatory mechanisms in adult NSCs using mouse as a model system. In particular, our recent studies have shown that the homeodomain transcription factor (TF) Gsx2 and basic helix-loop-helix TF Ascl1, which have been well known for their essential roles in embryonic brain development, play vital roles in controlling NSCs in the adult subventricular zone (SVZ). Importantly, we found that Gsx2 and Ascl1 control adult-specific regulatory steps in NSCs. We also have shown that these TFs play essential roles in injury-induced neurogenesis. Our preliminary studies further suggest that unlike in embryos in which Gsx2 and Ascl1 act in a linear cascade (Gsx2 ¿ Ascl1 ¿ neurogenesis), their cross-inhibition plays a key role in controlling the fate of adult NSCs. Based on these novel findings and in vivo tools, we will test the hypothesis that Gsx2 and Ascl1, as well as their downstream effectors, play crucial roles in controlling NSCs in adult-specific manners under intact and injury conditions in the following three specific aims: Aim 1 will reveal novel mechanisms for lineage progression of adult NSCs through studies on Gsx2, Ascl1, and their downstream targets. ; Aim 2 will reveal novel mechanisms for regional specification of NSCs and neuronal subtype specification of olfactory bulb (OB) interneurons through studies on the regulation of Gsx2 and its downstream factors.; Aim 3 will reveal novel mechanisms for injury-induced neurogenesis through studies on the regulation of the expression and action of Gsx2.

 描述（由申请人提供）：成年哺乳动物脑中的神经干细胞（NSC）已被证明在高级脑功能的可塑性以及脑损伤后的修复和再生中发挥重要作用。然而，我们对成体神经干细胞在分子水平上的调控的理解仍然是粗略的，这也是为什么利用内源性神经干细胞进行脑修复的策略尚未取得足够的临床应用进展的原因之一。本研究的目的是填补目前的知识空白，确定关键的调控机制，在成年神经干细胞使用小鼠作为模型系统。特别是，我们最近的研究表明，同源结构域转录因子（TF）Gsx 2和碱性螺旋-环-螺旋TF Ascl 1，这已被熟知的胚胎脑发育中的重要作用，在控制成年脑室下区（SVZ）的神经干细胞中发挥重要作用。重要的是，我们发现Gsx 2和Ascl 1控制神经干细胞中的成人特异性调节步骤。我们还表明，这些TF在损伤诱导的神经发生中发挥重要作用。我们的初步研究进一步表明，与Gsx 2和Ascl 1以线性级联（Gsx 2神经发生）作用的胚胎不同，它们的交叉抑制在控制成年NSC的命运中起着关键作用。基于这些新的发现和体内工具，我们将检验Gsx 2和Ascl 1及其下游效应子在完整和损伤条件下以成人特异性方式控制NSC中发挥关键作用的假设 具体目标有以下三个：目标1通过对Gsx 2、Ascl 1及其下游靶点的研究，揭示成体神经干细胞谱系进展的新机制。目的2通过对Gsx 2及其下游调控因子的研究，揭示神经干细胞区域分化和嗅球中间神经元亚型分化的新机制。目的3通过研究Gsx 2的表达和作用，揭示损伤诱导神经发生的新机制。