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Genomics/Proteomics of p53-mediated Neuronal Death

p53 介导的神经元死亡的基因组学/蛋白质组学

基本信息

批准号：
7173349
负责人：
MARK D JOHNSON
金额：
$ 16.57万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-15 至 2008-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7173349
关键词：
Abbreviations Adenovirus p53 Alzheimer&apos s Disease Apoptosis Apoptotic Blood capillaries Candidate Disease Gene Caspase Cell physiology Cells Cessation of life Chimeric Proteins Complex Coupled Cyclotrons Cysteine DNA Damage DNA Microarray Chip Data Doctor of Medicine Doctor of Philosophy Electrospray Ionization Exposure to Expressed Sequence Tags Fibroblasts Fluorescence Fourier Transform Gene Proteins Gene Targeting Genes Genetic Transcription Genomics Glutamates Green Fluorescent Proteins Huntington Disease Injury Investigation Ionizing radiation Ions Label Lead Liquid Chromatography Mass Spectrum Analysis Measurement Mediating Messenger RNA Methods Microarray Analysis Modeling Mus Neurodegenerative Disorders Neurons Numbers Parents Pathogenesis Pathway interactions Peptides Physiology Protein Overexpression Protein p53 Proteins Proteome Proteomics Purpose Relative (related person)Research Residencies Role Signal Pathway Site Spectrometry Speed Staging Staining method Stains Surveys TP53 gene Techniques Technology Tissue-Specific Gene Expression Trans-Activators Transcription Repressor/Corepressor Transfection Tumor Suppressor Proteins Universities Washington Western Blotting Wild Type Mouse Zinc Fingers annexin A5 cDNA Arrays capillary career chemotherapeutic agent design excitotoxicity expression vector immunocytochemistry imprint injured instructor instrumentation interest mRNA Expression mass spectrometer medical schools neuron apoptosis neuron loss neuronal survival neurosurgery neurotoxic polypeptide prevent programs protein expression research study skills transcription factor

项目摘要

DESCRIPTION (provided by applicant): The p53 protein is a site-specific transactivator or repressor of transcription that promotes apoptosis, in part, by modulating the expression of select target genes. Studies have implicated p53 in the pathogenesis of neuronal cell death occurring after DNA damage orexcitotoxicity, or in neurodegenerative diseases such as Huntington?s Disease and Alzheimer?s Disease. However, the cellular consequences of p53 activation in neurons are poorly understood, and a comprehensive survey of changes in gene and protein expression in neurons after p53 activation is therefore needed. This project will combine the use of cDNA microarray technology and Fourier transform ion cyclotron resonance mass spectrometric analysis of the proteome to rapidly and comprehensively characterize p53-dependent changes in mRNA and protein expression in cortical neurons derived from p53+/+ and p53-/- mice after genotoxic or excitotoxic injury. Proteins essential to p53-mediated neuronal cell death will be identified and investigated further to elucidate their function. One such gene product, Peg3, is a Kruppel-type zinc finger protein and putative transcription factor that has recently been implicated in p53-mediated apoptosis in fibroblasts. Using transient transfection or exposure to DNA damaging agents, Peg3 expression will be manipulated in cortical neurons derived from wild type, p53-/- or bax-/- mice, and the effects on neuronal cell death will be assessed. The study of Peg3 will serve as a model for the investigation of other p53-regulated gene products in neurons. The candidate has earned both the M.D. and Ph.D. degrees from Harvard Medical School, and is now nearing completion of a residency in neurosurgery at the University of Washington, where he has recently been appointed as an Acting Instructor. The proposed research represents a continuation of the candidate?s longstanding interest in the physiology and survival of neurons. The skills acquired will assist the candidate in establishing an independent research career to study the determinants, of neuronal survival, differentiation and function.

描述（由申请人提供）：p53 蛋白是一种位点特异性蛋白部分促进细胞凋亡的反式激活因子或转录抑制因子，通过调节选定目标基因的表达。研究表明 p53 在 DNA 损伤或兴奋性毒性后发生的神经细胞死亡的发病机制中，或在神经退行性疾病（如亨廷顿病和阿尔茨海默病）中发挥作用。然而，人们对神经元中 p53 激活的细胞后果知之甚少，因此需要对 p53 激活后神经元中基因和蛋白质表达的变化进行全面调查。该项目将结合利用cDNA微阵列技术和傅里叶变换离子回旋共振质谱分析蛋白质组快速、全面地表征 mRNA 和 p53 依赖性变化 p53+/+ 和 p53-/- 小鼠皮层神经元中的蛋白质表达遗传毒性或兴奋性毒性损伤后。 p53 介导所必需的蛋白质神经元细胞死亡将被识别并进一步研究以阐明他们的功能。其中一种基因产物 Peg3 是 Kruppel 型锌指最近与相关的蛋白质和推定的转录因子 p53 介导的成纤维细胞凋亡。使用瞬时转染或暴露对于 DNA 损伤剂，Peg3 的表达将在皮质神经元中受到控制源自野生型、p53-/- 或 bax-/- 小鼠，以及对神经元细胞的影响将评估死亡情况。 Peg3的研究将作为模型神经元中其他 p53 调节基因产物的研究。候选人已获得医学博士和博士学位。拥有哈佛医学院学位，并且是现在即将完成在大学的神经外科住院医师实习期华盛顿，他最近被任命为代理讲师。这拟议的研究代表了候选人长期研究的延续对神经元的生理学和生存感兴趣。获得的技能将协助候选人建立独立的研究生涯来学习神经元存活、分化和功能的决定因素。