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: 7773512
• 负责人: Patrizia Casaccia
• 金额: $ 36.71万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7773512
• 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; 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; 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; adult neurogenesis; 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; subventricular zone

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(申请人提供)：尽管干细胞疗法已被提出用于修复，但对这些细胞在成年损伤的中枢神经系统中的行为仍然知之甚少。众所周知，成年SVZ细胞的两种主要有丝分裂原对其行为有非常不同的影响：FGF2促进增殖并促进神经发生(Kuhn等人，1997)，而EGF促进增殖但以神经发生为代价(Doetsch等人，2002)，但下游信号通路仍然难以捉摸。P27Kip1和p53是SVZ细胞中FGF2和EGF激活的信号通路的下游效应因子，这两个重要的细胞周期调节因子在成体SVZ中表达，在胶质母细胞瘤中经常突变。这一假说是基于我们实验室对p27Kip1-/-和p53-/-小鼠进行的表型鉴定得出的遗传证据，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。基于我们的蛋白质组学和基因图谱研究的结果，我们进一步提出了一种分子机制，将这两个细胞周期基因整合到下游信号网络中，调节谱系决定和生存。因此，这项建议阐述了细胞周期分子p27Kip1和p53不仅调节成体祖细胞和成体脑室下区神经干细胞的增殖，而且调节成体祖细胞和神经干细胞的存活和谱系特征的新的分子机制。特异性目的1验证了一种假设，即成年SVZ中慢速和快速增殖细胞的细胞周期调控是由p27Kip1和p53差异调节的，并且这些分子位于FGF2和EGF的下游。特异性目的2验证了FGF2和EGF在成人神经发生中的相反作用依赖于它们对影响细胞命运决定的分子网络中的P53和P27Kip1的作用的假设。特异靶3将验证P53和p27Kip1在成年SVZ细胞的凋亡通路中发挥拮抗作用的假设。这些研究结果将极大地扩展我们目前对成年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被探索的角色，它们还将显著影响其他几个领域，包括发育神经生物学和临床神经生物学。