Yeast Genetics and Stress Response Genes-Biomedical

酵母遗传学和应激反应基因-生物医学

• 批准号: 6897642
• 负责人: PAUL RUSSELL
• 金额: $ 29.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897642
• 关键词: Schizosaccharomyces pombe; arsenic; biological models; biological signal transduction; biomarker; cadmium; environmental toxicology; eukaryote; functional /structural genomics; fungal genetics; gene environment interaction; gene expression; gene mutation; genetic mapping; genetic regulation; genetic screening; genetic strain; genetic transcription; hazardous substances; hydrogen peroxide; immune response genes; immunogenetics; microarray technology; oxidative stress; protein protein interaction

DESCRIPTION (provided by applicant): This proposal describes genetic and biochemical studies that are aimed at developing a better understanding of the effects of hazardous chemicals on eukaryotic organisms. The investigators want to decipher how eukaryotes sense hazardous chemicals and how they mount defensive responses. A central aim of these studies is to understand the signal transduction mechanisms that control gene expression in response to exposure to toxic chemicals. This type of knowledge will be crucial for understanding the effects of toxic chemicals on human health. A critical long-term goal of these studies will be the development of new strategies to improve detection of environmental toxins. Arsenic and cadmium will be emphasized in these investigations, although hydrogen peroxide will also be used as an efficient and specific method of inflicting oxidative stress. The fission yeast Schizosaccharomyces pombe will be used as the experimental organism for these studies. Fission yeast has be valuable model system for studying basic features of genotoxic and cytotoxic stress response mechanisms that are conserved amongst most eukaryotes, including mammals and plants. In the last funding period the investigators identified Csxl, a novel RNA-binding protein that controls global patterns of gene expression in response to oxidative stress In the upcoming funding period we propose to further these studies and to expand our area of investigation to include a functional genomics screen of genes whose expression is regulated in response to cadmium and arsenic exposure. They also plan to develop yeast strains that have arsenic and cadmium induced genes fused to readily detectable biomarkers. The project has three Specific Aims: 1) to understand how Csxl controls gene expression in response to oxidative stress. Csxl controls mRNA turnover during oxidative stress. All the mRNAs will be defined that are directly regulated by Csxl and investigate Cip1 and Cip2, two Csxl-interacting proteins. that play important roles in controlling gene expression in response to oxidative stress. The other Specific Aims are to 2) carry out a functional genomics screen to identify novel genes that play significant roles in tolerance of cadmium and arsenic, and 3) develop specific biomarkers for arsenic and cadmium.

描述（由申请人提供）：该提案描述了旨在更好地了解危险化学品对真核生物影响的遗传和生化研究。研究人员希望破译真核生物如何感知危险化学物质以及它们如何发起防御反应。 这些研究的中心目的是了解响应有毒化学物质暴露而控制基因表达的信号转导机制。此类知识对于了解有毒化学品对人类健康的影响至关重要。 这些研究的一个重要的长期目标是制定新策略来改进环境毒素的检测。 尽管过氧化氢也将被用作造成氧化应激的有效且具体的方法，但这些研究将重点关注砷和镉。裂殖酵母裂殖酵母 (Schizosaccharomyces pombe) 将用作这些实验的实验生物体 研究。 裂殖酵母是研究大多数真核生物（包括哺乳动物和植物）中保守的基因毒性和细胞毒性应激反应机制基本特征的有价值的模型系统。 在上一个资助期内，研究人员发现了 Csxl，一种新型 RNA 结合蛋白，可控制基因表达的整体模式以应对氧化应激。在即将到来的资助期内，我们建议进一步开展这些研究，并扩大我们的研究领域，包括对镉和砷暴露反应中表达受到调节的基因进行功能基因组学筛选。他们还计划开发具有砷和镉诱导基因与易于检测的生物标志物融合的酵母菌株。 该项目有三个具体目标：1) 了解 Csxl 如何控制基因表达以应对氧化应激。 Csxl 控制氧化应激期间 mRNA 的周转。 所有受 Csxl 直接调节的 mRNA 都将被定义，并研究 Cip1 和 Cip2（两种 Csxl 相互作用蛋白）。在控制基因表达中发挥重要作用 对氧化应激的反应。其他具体目标是 2) 进行功能基因组学筛选，以确定在镉和砷耐受性中发挥重要作用的新基因，以及 3) 开发砷和镉的特异性生物标志物。