Role of cell cycle inhibitors in adult neural stem cells

细胞周期抑制剂在成体神经干细胞中的作用

• 批准号: 7437287
• 负责人: Patrizia Casaccia
• 金额: $ 1.36万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7437287
• 关键词: Address; Adult; Affect; Apoptosis; Apoptotic; Behavior; Binding; Brain Neoplasms; Cell Cycle; Cell Cycle Regulation; Cell division; Cells; Cessation of life; Clinical; Cytosine; Data; Developmental Biology; Differentiation Inhibitor; EGF gene; FGF2 gene; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Gene Expression; Genes; Genetic; Genomics; Glioblastoma; In Vitro; Infusion procedures; Injection of therapeutic agent; Knock-out; Knockout Mice; Knowledge; Label; Laboratories; Link; Malignant - descriptor; Mediator of activation protein; Mitogens; Modeling; Molecular; Mus; Mutate; Neoplastic Cell Transformation; Neurobiology; Pathway interactions; Pattern; Personal Satisfaction; Phenotype; Play; Population; Proliferating; Proteomics; Regulatory Pathway; Relative (related person); Reporter; Research Personnel; Role; Screening procedure; Signal Pathway; Signal Transduction; TP53 gene; Testing; Time; Transcriptional Regulation; Wild Type Mouse; base; cdc Genes; cell behavior; cell type; developmental neurobiology; in vivo; inhibitor/antagonist; injured; insight; nerve stem cell; neurogenesis; novel; progenitor; programs; relating to nervous system; repaired; research study; self-renewal; stem cell therapy

DESCRIPTION (provided by applicant): Although stem cell therapy has been proposed for repair, still relatively little is known about the behavior of these cells in the adult injured CNS. It is well accepted that two major mitogens for adult SVZ cells have very different effects on their behavior: FGF2 increases proliferation and favors neurogenesis (Kuhn et al., 1997), while EGF increases proliferation at the expenses of neurogenesis (Doetsch et al., 2002), but the downstream signaling pathways remain elusive. This proposal tests the hypothesis that p27Kip1 and p53, two crucial cell cycle regulators which are expressed in the adult SVZ and often mutated in glioblastomas, are downstream effectors of signaling pathways activated by FGF2 and EGF in SVZ cells. This hypothesis is based on genetic evidence derived from the phenotypic characterization of p27Kip1-/- and in p53-/- mice, conducted in our laboratory and indicating a close similarity between the phenotype of p53-/- mice and FGF2 injection, and that of p27Kip1-/- mice and EGF injection. We further propose, based on the results of our proteomic and gene profiling studies, a molecular mechanism integrating these two cell cycle genes within downstream signaling networks that modulate lineage determination and survival. Therefore, this proposal addresses novel molecular mechanisms for the role of the cell cycle molecules p27Kip1 and p53 in modulating not only proliferation, but also survival and lineage specification of adult progenitors and neural stem cells residing in the adult subventricular zone (SVZ). Specific aim 1 tests the hypothesis that cell cycle regulation of slow and fast-proliferating cells in the adult SVZ is differentially modulated by p27Kip1 and p53 and that these molecules are downstream of FGF2 and EGF. Specific aim 2 tests the hypothesis that the opposing role of FGF2 and EGF on adult neurogenesis is dependent on their effect on p53 and p27Kip1 which play antagonistic roles on molecular networks affecting cell fate determination. Specific aim 3 will test the hypothesis that p53 and p27Kip1 exert antagonistic functions on apoptotic pathways in adult SVZ cells. The results of the proposed studies will significantly extend our current knowledge on the mechanisms of cell division and neoplastic transformation of adult SVZ cells. In addition, by addressing novel and unexplored roles for p27Kip and p53 as part of transcriptional networks and signaling pathways, they will also significantly impact several other fields, including developmental neurobiology and clinical neurobiology.

描述（由申请人提供）：尽管干细胞疗法已被提议用于修复，但对于这些细胞在成人受伤中枢神经系统中的行为仍然知之甚少。人们普遍认为，成年 SVZ 细胞的两种主要有丝分裂原对其行为具有截然不同的影响：FGF2 增加增殖并有利于神经发生（Kuhn 等，1997），而 EGF 增加增殖但牺牲神经发生（Doetsch 等，2002），但下游信号通路仍然难以捉摸。该提案测试了以下假设：p27Kip1 和 p53（在成人 SVZ 中表达并经常在胶质母细胞瘤中突变的两种关键细胞周期调节因子）是 SVZ 细胞中 FGF2 和 EGF 激活的信号通路的下游效应器。这一假设基于我们实验室进行的 p27Kip1-/- 和 p53-/- 小鼠表型特征的遗传证据，表明 p53-/- 小鼠和 FGF2 注射的表型与 p27Kip1-/- 小鼠和 EGF 注射的表型非常相似。根据我们的蛋白质组学和基因分析研究的结果，我们进一步提出了一种将这两个细胞周期基因整合到调节谱系决定和存活的下游信号网络中的分子机制。因此，该提案提出了细胞周期分子 p27Kip1 和 p53 的作用的新分子机制，不仅调节增殖，而且调节位于成体室下区 (SVZ) 的成体祖细胞和神经干细胞的存活和谱系规范。具体目标 1 检验以下假设：成人 SVZ 中缓慢和快速增殖细胞的细胞周期调节受到 p27Kip1 和 p53 的差异调节，并且这些分子是 FGF2 和 EGF 的下游。具体目标 2 测试了以下假设：FGF2 和 EGF 对成体神经发生的相反作用取决于它们对 p53 和 p27Kip1 的影响，而 p53 和 p27Kip1 在影响细胞命运决定的分子网络上发挥拮抗作用。具体目标 3 将检验 p53 和 p27Kip1 对成年 SVZ 细胞的凋亡途径发挥拮抗功能的假设。所提出的研究结果将显着扩展我们目前对成体 SVZ 细胞分裂和肿瘤转化机制的认识。此外，通过解决 p27Kip 和 p53 作为转录网络和信号通路一部分的新的和未探索的作用，它们还将对其他几个领域产生重大影响，包括发育神经生物学和临床神经生物学。