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

基本信息

批准号：
7289928
负责人：
JAMES A COFFMAN
金额：
$ 21.87万
依托单位：
MOUNT DESERT ISLAND BIOLOGICAL LAB
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7289928
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 Localized MAPK14 gene Mediating Messenger RNA Metals Mitochondria Mitogen-Activated Protein Kinases Modeling Molecular Nervous system structure Neurons Nodal Numbers Oral Oxidation-Reduction Oxidative Stress Pathology Pathway Analysis Pathway interactions Pattern Phosphoric Monoester Hydrolases Phylogenetic Analysis Physiology Predisposition Production Protein phosphatase Publishing Reactive Oxygen Species Reagent Regulator Genes Regulatory Element Regulatory Pathway Research Research Personnel Role playing therapy Sea Urchins Signal Pathway Signal Transduction Specific qualifier value Speed Stress System Technology Teratogens Testing Toxicogenomics Transcript Transcription Regulatory Protein Translations base comparative egg environmental stressor genome sequencing human MAPK14 protein human disease malformation mitogen-activated protein kinase p38 neurodevelopment oral ectoderm response stressor transcription factor

项目摘要

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）：该项目的目的是阐明氧化还原响应性的发育途径和基因调节网络，以介导对环境氧化还原应激源的敏感性。氧化还原化学是生物学的核心，它提供了富含生命的能量，但也以活性氧（ROS）的形式产生有毒的副产品。 ROS产生会导致氧化应激，这是许多人类疾病（例如糖尿病）和环境诱发的病理（例如与酗酒相关的疾病）的标志。因此，生物信号系统通常对氧化还原化学反应。虽然已知许多环境氧化还原压力源也会引起人类的发育畸形，尤其是在发展中的神经系统中，但介导这种敏感性的氧化还原敏感的调节网络在很大程度上尚不清楚。海胆胚胎提供了一个有用的比较模型来解决该问题，因为它的基因组已被测序和注释，并且由于它是氘代表仪，因此与其他无脊椎动物模型生物体相比，它与人类的发展更为相似。许多发现表明，沿海胆胚胎的口腔 - 栖息轴外胚层细胞命运是通过氧化还原敏感的调节网络指定的，并且可以通过金属离子和低氧氧化物等氧化还原应激源特异性地扰动（放射性）。外皮细胞命运规范是由淋巴结信号传导介导的，这反过来取决于p38有丝分裂原活化蛋白激酶（MARK）。该项目的具体目的是（1）检验以下假设：p38有丝分裂激活的蛋白激酶（MARK）活性受发育中的外胚层中的氧化还原信号传导调节；（2）确定调节淋巴结活性的氧化还原响应的顺式元素和转录因子；（3）确定氧化还原应激源扰动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性的分子试剂，包括线粒体靶向酶促抗氧化剂，吗啡抗抗抗氧化剂的介导的敲低和对淋巴结基因的顺式调节分析。另外，将使用微阵列方法来识别氧化还原敏感的转录组。最后，将使用MDIBL的比较毒物学数据库（CTD）来确定在海胆中发现的途径与人类健康中发现的途径的相关性，并产生可能解释特定人类疾病的假设。