Rest-Activated Program of Gene Expression in Ischemia

REST/NRSF是一种基因沉默转录因子，在胚胎发育过程中广泛表达，并在 在终末神经元分化中的战略作用。在神经前体细胞和非神经细胞中，REST积极抑制 大量对突触可塑性和突触重构重要的神经特异性基因，包括编码这些基因的基因 突触小泡蛋白、结构蛋白、电压敏感离子通道和AMPAR亚单位GluR2。AS 神经元分化、静息下调对神经表型的诱导和维持至关重要。 胚胎发育过程中REST表达的干扰会导致细胞凋亡、异常分化和 图案化和杀伤力。REST及其靶基因的失调与唐氏症的发病有关 综合征，艾兹海默氏病和一些髓母细胞瘤。全脑缺血是一种神经紊乱，在这种情况下 短暂的神经元损伤可导致海马区CA1区神经元选择性延迟性死亡。两国之间的重大延误 侮辱和细胞死亡与转录变化的作用是一致的。这个实验室的最新发现表明 缺血损伤激活注定要死亡的神经元的静息，并在全脑缺血诱导的神经元中牵连静息 死亡。这项拟议的研究旨在研究REST启动的转录变化程序在 缺血症。AMPAR亚基GluR2、脑源性神经营养因子(BDNF)和β阿片受体是已知的 静息靶点和与全脑缺血相关的兴奋性死亡有关。重点将是休息- 依赖性沉默GluR2和p受体基因表达，上调BDNF表达。潜在的 假说是全球缺血触发了基因沉默转录因子REST的下调，从而启动了 一种基因转录变化的程序，并且一个或多个REST靶基因是全球 缺血诱导的神经元死亡。具体目标是1)检查REST抑制物复合体在术后的激活 并确定休息是否与神经元死亡有因果关系。2)通过以下方式检查机制 哪些REST改变了缺血后神经元的靶基因，并决定了REST依赖的染色质 重塑与神经元死亡有因果关系；以及3)识别新的休息靶基因并确定它们是否 与神经元死亡有因果关系。我们的发现与观察到的转录失调是一致的。 并提示静息沉默的中断在全脑缺血的发病机制中起着关键作用。 这项拟议的研究将影响新的干预全球缺血的治疗策略的开发， 每年影响20万美国人的恢复性创伤。这项研究对其他方面的研究也有意义 疾病包括癫痫、中风、创伤性脑损伤、脊髓损伤和阿尔茨海默病。

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, AIzheimer'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 p 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.