Programmed Cell Death and DNA Damage Signals

程序性细胞死亡和 DNA 损伤信号

• 批准号: 7067154
• 负责人: JANICE Rae NAEGELE
• 金额: $ 25.81万
• 依托单位: WESLEYAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067154
• 关键词: DNA damage; DNA repair; apoptosis; biological signal transduction; cell differentiation; cell type; cerebral cortex; developmental neurobiology; embryo /fetus; free radical scavengers; free radicals; gene targeting; genetically modified animals; growth factor; hypoxia; laboratory mouse; neurogenesis; neurons; neurotoxins; p53 gene /protein; tissue /cell culture

DESCRIPTION (provided by applicant): Our long-term objective is to understand how programmed cell death and DNA repair guide development and maintenance of the nervous system. This ROl focuses a specific form of DNA repair called Non-Homologous End Joining (NHEJ), which is required for proper development of the CNS. Enzymes involved in NHEJ and other DNA repairs serve critical roles in genomic stability and neuronal survival in neurodegenerative disorders such as Alzheimer's and ALS. In the developing brain, programmed cell death is regulated process acting in concert with neurogenesis and differentiation. Knockout mice deficient NHEJ or other DNA repair processes typically have increased apoptosis in the embryonic CNS and perinatal lethality. We will utilize NHEJ deficient mice in combination with cellular and molecular approaches to study the impact of genomic instability on neuronal survival and differentiation. To accomplish this broad goal, we have four Specific aims. The first proposes to compare the molecular phenotypes of neural progenitors and postmitotic neurons in the cerebral cortex of normal and NHEJ-deficient mouse embryos. We will monitor cell death and examine the expression of cell cycle and other molecular markers. We will also generate CNS-specific conditional knockouts of NHEJ genes using cre-recombinase technology to evaluate whether failed NHEJ in neural progenitors and neurons is responsible for the differences in apoptosis. The second aim will determine if NHEJ deficient embryonic CNS cultures exhibit increased apoptotic responses to hypoxia, free radical damage, or excitotoxic injury. The third aim will examine whether NHEJ deficiency and accumulated DNA breaks coupled with hypoxia or excitotoxic injury activate p53 and downstream apoptotic effects such as mitochondrial dysfunction. We will generate compound knockout mice lacking NHEJ genes and either p53 or Bax to test this hypothesis. Our fourth aim will extend these studies to ask whether exogenous growth factors or free radical scavengers can delay or prevents downstream apoptotic signaling in NHEJ deficient mice.

描述（由申请人提供）：我们的长期目标是了解程序性细胞死亡和 DNA 修复如何指导神经系统的发育和维护。该RO1集中于称为非同源末端连接(NHEJ)的特定形式的DNA修复，其是CNS的正常发育所必需的。参与 NHEJ 和其他 DNA 修复的酶在阿尔茨海默病和 ALS 等神经退行性疾病的基因组稳定性和神经元存活中发挥着关键作用。在发育中的大脑中，程序性细胞死亡是与神经发生和分化协同作用的调节过程。 NHEJ 或其他 DNA 修复过程缺陷的基因敲除小鼠通常会增加胚胎中枢神经系统的细胞凋亡和围产期死亡率。我们将利用 NHEJ 缺陷小鼠结合细胞和分子方法来研究基因组不稳定性对神经元存活和分化的影响。为了实现这一总体目标，我们有四个具体目标。第一个建议比较正常和 NHEJ 缺陷小鼠胚胎大脑皮层中神经祖细胞和有丝分裂后神经元的分子表型。我们将监测细胞死亡并检查细胞周期和其他分子标记的表达。我们还将使用 cre 重组酶技术生成 CNS 特异性 NHEJ 基因的条件敲除，以评估神经祖细胞和神经元中失败的 NHEJ 是否导致细胞凋亡的差异。第二个目标将确定 NHEJ 缺陷的胚胎中枢神经系统培养物是否表现出对缺氧、自由基损伤或兴奋性毒性损伤的细胞凋亡反应增加。第三个目标将检查 NHEJ 缺陷和累积的 DNA 断裂以及缺氧或兴奋性毒性损伤是否会激活 p53 和下游细胞凋亡效应（例如线粒体功能障碍）。我们将生成缺乏 NHEJ 基因和 p53 或 Bax 的复合敲除小鼠来检验这一假设。我们的第四个目标是扩展这些研究，探究外源生长因子或自由基清除剂是否可以延迟或阻止 NHEJ 缺陷小鼠的下游凋亡信号传导。

项目成果

Differentiation and functional incorporation of embryonic stem cell-derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy.

• DOI: 10.1523/jneurosci.2683-11.2012
• 发表时间: 2012-01-04
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Maisano X;Litvina E;Tagliatela S;Aaron GB;Grabel LB;Naegele JR
• 通讯作者: Naegele JR

The DNA-PK catalytic subunit regulates Bax-mediated excitotoxic cell death by Ku70 phosphorylation.

• DOI: 10.1016/j.brainres.2009.07.101
• 发表时间: 2009-11-03
• 期刊: BRAIN RESEARCH
• 影响因子: 2.9
• 作者: Liu, Jia;Naegele, Janice R.;Lin, Stanley L.
• 通讯作者: Lin, Stanley L.

Recent advancements in stem cell and gene therapies for neurological disorders and intractable epilepsy.

• DOI: 10.1016/j.neuropharm.2010.01.019
• 发表时间: 2010-05
• 期刊: NEUROPHARMACOLOGY
• 影响因子: 4.7
• 作者: Naegele, Janice R.;Maisano, Xu;Yang, Jia;Royston, Sara;Ribeiro, Efrain
• 通讯作者: Ribeiro, Efrain

Elevated DNA double strand breaks and apoptosis in the CNS of scid mutant mice.

scid 突变小鼠中枢神经系统 DNA 双链断裂和细胞凋亡升高。

• DOI: 10.1038/sj.cdd.4400806
• 发表时间: 2001
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Vemuri,MC;Schiller,E;Naegele,JR
• 通讯作者: Naegele,JR

Embryonic stem cell-derived neural precursor grafts for treatment of temporal lobe epilepsy.

胚胎干细胞衍生的神经前体移植物用于治疗颞叶癫痫。

• DOI: 10.1016/j.nurt.2009.01.011
• 发表时间: 2009
• 期刊: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
• 作者: Maisano,Xu;Carpentino,Joseph;Becker,Sandy;Lanza,Robert;Aaron,Gloster;Grabel,Laura;Naegele,JaniceR
• 通讯作者: Naegele,JaniceR