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Identification and functional characterization of ATF3 target genes that mediate neuronal survival

介导神经元存活的 ATF3 靶基因的鉴定和功能表征

基本信息

批准号：
60352071
负责人：
Professor Dr. Hilmar Bading
金额：
--
依托单位：
Interdisziplinäres Zentrum für Neurowissenschaften (IZN)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2010-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/60352071?language=en
关键词：
Identification functional characterization ATF3 target

项目摘要

Neuronal activity and NMDA receptor activation are critical for the survival of neurons. Although the precise mechanisms involved in this process are unknown, activity-induced nuclear calcium transients and gene expression mediated by the transcription factor CREB are important. Whole genome transcriptional profiling led to the discovery of a nuclear calcium-regulated, multi-component genomic survival program. The CREB target ATF3 plays a central role in this program; it acts as a transcriptional repressor and confers neuroprotection through down-regulation of genes. The aim of the project is to identify the ATF3 targets that mediate neuroprotection. We propose two experimental strategies: an unbiased search for ATF3 target genes as well as an analysis of the putative ATF3 target gene, Trpm7, a non-selective cation channel with a role in cell death. We will use whole genome transcriptome analysis to identify all genes regulated by ATF3 in hippocampal neurons and, using gene ontology searches, filter out those genes that have a possible role in apoptosis or survival. Expression of Trpm7 upon electrical activation of hippocampal neurons follows an expression profile consistent with it being a target of ATF3. We will investigate the regulation of all candidate target genes (including Trpm7) by nuclear calcium-CREB-ATF3 signaling and assess their role in neuronal survival in vitro and in vivo. This study may lead to the identification of novel gene targets for the development of neuroprotective therapies for neurodegenerative diseases.

神经元活性和NMDA受体活化对于神经元的存活至关重要。虽然在这个过程中涉及的确切机制是未知的，活动诱导的核钙瞬变和转录因子CREB介导的基因表达是重要的。全基因组转录谱分析导致了核钙调节的多组分基因组存活程序的发现。CREB靶点ATF 3在该程序中起核心作用;它作为转录抑制因子，通过下调基因赋予神经保护作用。该项目的目的是确定介导神经保护的ATF 3靶点。我们提出了两个实验策略：一个公正的搜索ATF 3的靶基因，以及分析推定的ATF 3的靶基因，Trpm 7，一个非选择性阳离子通道与细胞死亡的作用。我们将使用全基因组转录组分析来识别海马神经元中受ATF 3调控的所有基因，并使用基因本体论搜索，筛选出那些在凋亡或存活中可能起作用的基因。海马神经元电激活后Trpm 7的表达遵循与其为ATF 3的靶标一致的表达谱。我们将研究所有候选靶基因（包括Trpm 7）通过核钙-CREB-ATF 3信号传导的调节，并评估它们在体外和体内神经元存活中的作用。这项研究可能会导致识别新的基因靶点，用于开发神经退行性疾病的神经保护疗法。