Redox-sensitive developmental pathways and gene regulatory networks

氧化还原敏感的发育途径和基因调控网络

• 批准号: 7629068
• 负责人: JAMES A COFFMAN
• 金额: $ 22.04万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629068
• 关键词: Address; Affect; Alcohol abuse; Animal Model; Animals; Antioxidants; Biochemical; Biological; Biological Models; Biology; California; Cells; Chemistry; Chromosome Mapping; Comparative Biology; Control Animal; Data; Databases; Defect; Development; Diabetes Mellitus; Disease; Dose; Ectoderm; Ectoderm Cell; Elements; Embryo; Event; Evolution; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Goals; Health; Human; Human Development; Hypoxia; Individual; Institutes; Invertebrates; Ions; Knowledge; Laboratories; Lead; Life; Literature; MAPK14 gene; Mediating; Messenger RNA; Metals; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular; Nervous system structure; Nodal; Oral; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway Analysis; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Phylogenetic Analysis; Physiology; Play; Predisposition; Production; Protein phosphatase; Publishing; Reactive Oxygen Species; Reagent; Regulator Genes; Regulatory Element; Regulatory Pathway; Research; Research Personnel; Role; Sea Urchins; Signal Pathway; Signal Transduction; Specific qualifier value; Speed; Stress; System; Technology; Teratogens; Testing; Toxicogenomics; Transcript; Transcription Regulatory Protein; Translational Research; base; cell fate specification; comparative; egg; environmental stressor; genome sequencing; human MAPK14 protein; human disease; malformation; mitogen-activated protein kinase p38; neurodevelopment; neuronal patterning; oral ectoderm; response; stressor; transcription factor

DESCRIPTION (provided by applicant): The goal of this project is to elucidate redox-responsive developmental pathways and gene regulatory networks that mediate susceptibility to environmental redox stressors. Redox chemistry is at the core of biology, providing the energy that fuels life but also producing toxic byproducts in the form of reactive oxygen species (ROS). ROS production can lead to oxidative stress, a hallmark of many human diseases (such as diabetes) and environmentally-induced pathologies (such as those associated with alcohol abuse). Biological signaling systems are therefore often responsive to redox chemistry. While many environmental redox stressors are also known to cause developmental malformations in humans, particularly in the developing nervous system, the redox-sensitive regulatory networks that mediate this susceptibility are largely unknown. The sea urchin embryo provides a useful comparative model for addressing this problem, as its genome has been sequenced and annotated, and because of the fact that it is a deuterostome and hence developmentally more similar to humans than other invertebrate model organisms. A number of findings indicate that ectodermal cell fate along the oral-aboral axis of the sea urchin embryo is specified via a redox-sensitive regulatory network, and can be specifically perturbed (radialized) by redox stressors such as metal ions and hypoxia. Ectodermal cell fate specification is mediated by Nodal signaling, which in turn is dependent on p38 mitogen activated protein kinase (MARK). The specific aims of this project are to (1) test the hypothesis that p38 mitogen activated protein kinase (MARK) activity is regulated by redox signaling in the developing ectoderm; (2) identify redox-responsive cis-elements and transcription factors that regulate Nodal activity; and (3) identify pathways through which redox stressors perturb ectodermal patterning and affect human development and disease. To achieve these aims, the project will make use of highly specific molecular reagents including mitochondrially-targeted enzymatic anti-oxidants, morpholino-antisense mediated knockdown, and cis-regulatory analysis of the Nodal gene. In addition, a microarray approach will be used to identify the redox-sensitive transcriptome. Finally, the Comparative Toxicogenomics Database (CTD) at MDIBL will be used to determine the relevance of the pathways discovered in sea urchins to human health, and to generate hypotheses that might explain specific human diseases.

描述(由申请人提供)： 这个项目的目标是阐明氧化还原反应的发育途径和基因调控网络，它们介导了对环境氧化还原应激源的易感性。氧化还原化学是生物学的核心，它为生命提供能量，但也会产生以活性氧(ROS)形式存在的有毒副产品。ROS的产生可导致氧化应激，这是许多人类疾病(如糖尿病)和环境引起的病理(如与酗酒有关的疾病)的标志。因此，生物信号系统通常对氧化还原化学作出反应。虽然已知许多环境氧化还原应激源也会导致人类发育畸形，特别是在发育中的神经系统，但调节这种易感性的氧化还原敏感调控网络在很大程度上是未知的。海胆胚胎为解决这一问题提供了一个有用的比较模型，因为它的基因组已经被测序和注释，而且因为它是后口动物，因此在发育上比其他无脊椎动物模式生物更接近人类。许多研究结果表明，海胆胚胎口腔-流产轴上的外胚层细胞命运是通过氧化还原敏感的调控网络决定的，并可以被氧化还原应激源(如金属离子和低氧)特异性地干扰(辐射)。外胚层细胞命运的决定是由Nodal信号介导的，而Nodal信号又依赖于p38丝裂原活化蛋白激酶(MARK)。该项目的具体目标是：(1)验证p38丝裂原活化蛋白激酶(MARK)活性受发育外胚层氧化还原信号调节的假说；(2)确定调节Nodal活性的氧化还原响应顺式元件和转录因子；(3)确定氧化还原应激物扰乱外胚层模式并影响人类发育和疾病的途径。为了实现这些目标，该项目将利用高度特异的分子试剂，包括线粒体靶向的酶抗氧化剂、吗啉反义介导的基因敲除和Nodal基因的顺式调控分析。此外，将使用微阵列方法来鉴定氧化还原敏感的转录组。最后，MDIBL的比较毒理基因组学数据库(CTD)将用于确定在海胆中发现的途径与人类健康的相关性，并产生可能解释特定人类疾病的假说。