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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：
7496998
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
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7496998
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）：