Rest-Activated Program of Gene Expression in Ischemia

缺血中基因表达的休息激活程序

• 批准号: 7039185
• 负责人: R. Suzanne Zukin
• 金额: $ 37.71万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039185
• 关键词: AMPA receptors; brain derived neurotrophic factor; cell death; chromatin; electrophysiology; gene expression; gene expression profiling; gene induction /repression; hippocampus; histology; ischemia; laboratory rat; nervous system disorder; neurons; opioid receptor; receptor expression; transcription factor

DESCRIPTION (provided by applicant): REST/NRSF is a gene silencing transcription factor that is widely expressed during embryogenesis and plays a strategic role in terminal neuronal differentiation. In neural progenitors and non-neural cells, REST actively represses a large array of neural-specific genes important to synaptic plasticity and synaptic remodeling including those encoding synaptic vesicle proteins, structural proteins, voltage-sensitive ion channels, and the AMPAR subunit GluR2. As neurons differentiate, REST downregulation is essential for induction and maintenance of the neural phenotype. Perturbation of REST expression during embryogenesis results in cellular apoptosis, aberrant differentiation and patterning, and lethality. Dysregulation of REST and its target genes is implicated in the pathogenesis of Down's syndrome, Alzheimer's disease and some medulloblastomas. Global ischemia is a neurological disorder in which a brief neuronal insult induces selective, delayed death of hippocampal CA1 neurons. The substantial delay between insult and cell death is consistent with a role for transcriptional changes. Recent findings from this laboratory show that ischemic insults activate REST in neurons destined to die and implicate REST in global ischemia-induced neuronal death. The proposed research aims to study the role of the REST-initiated program of transcriptional changes in ischemia. The AMPAR subunit GluR2, brain-derived neurotrophic factor (BDNF) and the u opioid receptor are known targets of REST and are implicated in the excitotoxic death associated with global ischemia. A focus will be REST-dependent silencing of GluR2 and p receptor gene expression and upregulation of BDNF expression. The underlying hypothesis is that global ischemia triggers de-repression of the gene silencing transcription factor REST, which initiates a program of gene transcriptional changes and that one or more REST target genes are critical players in global ischemia-induced neuronal death. Specific Aims are 1) Examine activation of the REST repressor complex in post-ischemic CA1 neurons and determine whether REST is causally related to neuronal death. 2) Examine mechanisms by which REST alters target genes in post-ischemic neurons and determine whether REST-dependent chromatin remodeling is causally related to neuronal death; and 3) Identify novel REST target genes and determine whether they are causally related to neuronal death. Our findings are consistent with observations of transcriptional dysregulation in injured neurons and suggest that disruption of REST silencing has a critical role in the pathogenesis of global ischemia. The proposed research will impact on the development of new treatment strategies for intervention in global ischemia, a dehabilitating trauma that affects 200,000 Americans each year. This study has implications for research on other disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury and Alzheimer's disease.

描述（由申请人提供）：REST/NRSF是一种基因沉默转录因子，在胚胎发生过程中广泛表达，并在末端神经元分化中起战略作用。在神经祖细胞和非神经细胞中，REST主动抑制一大批对突触可塑性和突触重塑重要的神经特异性基因，包括那些编码突触囊泡蛋白，结构性蛋白质，电压敏感的离子通道以及AMPAR亚基GlUR2。随着神经元的区分，休息下调对于诱导和维持神经表型至关重要。胚胎发生过程中休息表达的扰动导致细胞凋亡，异常分化和模式以及致死性。静止及其靶基因的失调与唐氏综合症，阿尔茨海默氏病和一些髓母细胞瘤的发病机理有关。全球性缺血是一种神经系统疾病，其中短暂的神经侮辱会诱导海马CA1神经元的选择性，延迟死亡。侮辱和细胞死亡之间的实质性延迟与转录变化的作用一致。该实验室的最新发现表明，缺血性损伤激活了原定死亡的神经元中的休息，并在全球缺血引起的神经元死亡中静止。拟议的研究旨在研究缺血中静止发起的转录变化计划的作用。 AMPAR亚基GLUR2，脑衍生的神经营养因子（BDNF）和U阿片类药物受体是已知的静止靶标，并且与与全球缺血有关的兴奋性死亡有关。焦点将是对GlUR2和P受体基因表达和BDNF表达的上调的静止依赖性沉默。基本的假设是，全球缺血触发了基因沉默转录因子休息的抑制，该基因启动了基因转录变化程序，并且一个或多个REST目标基因是全球缺血性神经元死亡的关键参与者。具体目的是1）检查缺血后CA1神经元中休息器复合物的激活，并确定REST是否与神经元死亡有因果关系。 2）检查静止性神经元中靶基因的机制，并确定静止依赖性染色质重塑是否与神经元死亡有因果关系； 3）确定新颖的REST靶基因，并确定它们是否与神经元死亡有因果关系。我们的发现与受伤神经元中转录失调的观察结果一致，并表明休息沉默的破坏在全球缺血的发病机理中起着至关重要的作用。拟议的研究将影响全球缺血干预新治疗策略的制定，这是每年影响20万美国人的消除创伤。这项研究对其他疾病的研究具有影响，包括癫痫，中风，脑损伤，脊髓损伤和阿尔茨海默氏病。