In vivo systems level analysis of gene-environment interactions

描述(由申请人提供)： 这个RC4应用程序涉及三个主题领域。主题领域1，应用基因组学和其他高通量技术，呼吁通过使用DNA测序、微阵列技术、新的成像模式和计算生物学在理解疾病机制方面取得重大进展。专题领域2，将基础科学发现转化为新的和更好的治疗方法，挑战研究界通过高通量筛查开发新的诊断和治疗策略。主题领域#5，重振生物医学研究社区，呼吁新的和创新的多学科合作，以解决最具挑战性的生物医学和行为问题。拟议的项目将通过创建一个自动化的高通量快速评估斑马鱼实验室来解决这些主题领域，研究人员可以在其中探索基因、化学物质和疾病之间的相互作用。该实验室每天将至少10,000条斑马鱼暴露在图书馆的化学物质中，并观察它们的行为和解剖反应。当这些化学物质引起反应时，研究人员将利用独特的基因组工具来阐明导致这种反应的一系列事件。因此，他们将从机制上了解斑马鱼对这种化学物质的反应，并识别维持生命或导致病理的生物分子网络。与对啮齿动物进行的类似研究相比，高通量设备将使成本降低四个数量级，持续时间减少两个数量级。拟议的项目将通过提高胚胎生产和处理速度、无特定病原体的水系统的能力、自动化行为和组织学终点以及基因组、代谢和表观遗传学分析的吞吐量，来增加辛胡伯水产研究实验室斑马鱼设施的生产能力。拟议中的设施将是第一个能够支持在整个脊椎动物发育背景下高通量研究基因、化学物质和疾病之间相互作用的机构。它将同样有利于毒物学家探索环境应激源的影响，药理学家开发新药，以及遗传学家希望识别未知基因的功能和相互作用。拟建的高通量设施将成为现代基因组研究的罗塞塔之石。它将提供快速而廉价的技术来阐明斑马鱼的生物分子网络。研究界将把这些知识转化为破译人类基因组的工作原理及其与环境的相互作用。 公共卫生相关性： 在这个高通量设施中进行的研究将产生对基因、化学物质和疾病之间关系的机械性理解，从而为新的治疗干预产生有用的假设和目标。这项工作将带来更好的预防、治疗和治愈疾病的方法。通过大幅降低进行机械性毒理学研究所需的成本和时间，该设施将使测试美国公众暴露在商业产品中的所有7万种化学物质的毒性在经济上可行。目前的程序每年只评估大约60种化学物质。

DESCRIPTION (provided by applicant): This RC4 application addresses three Thematic Areas. Thematic Area #1, Applying Genomics and Other High-Throughput Technologies, calls for major advances in the understanding of the mechanisms of diseases through the use of DNA sequencing, microarray technology, new imaging modalities, and computational biology. Thematic Area #2, Translating Basic Science Discoveries into New and Better Treatments, challenges the research community to develop new diagnostic and therapeutic strategies via high-throughput screening. Thematic Area #5, Reinvigorating the Biomedical Research Community, calls for new and innovative multi-disciplinary collaborations to solve the most challenging biomedical and behavioral issues. The proposed project will address these Thematic Areas by creating an automated high-throughput rapid- assessment zebrafish laboratory in which researchers can explore the interactions among genes, chemicals, and diseases. This laboratory will expose at least 10,000 zebrafish per day to chemicals from libraries and observe their behavioral and anatomical responses. When the chemicals evoke a response, researchers will exploit unique genomic tools to elucidate the sequence of events that led to it. They will thereby gain a mechanistic understanding of the zebrafish's response to the chemical and also identify the biomolecular networks that sustain life or result in pathology. Compared with analogous studies in rodents, the high- throughput facility will reduce the cost by four orders of magnitude and the duration by two orders of magnitude. The proposed project will increase the throughput of the zebrafish facility at the Sinnhuber Aquatic Research laboratory by increasing the rates of embryo production and handling, the capacity of the specific- pathogen-free water system, automating behavioral and histological endpoints, and the throughput for genomic, metabolomic, and epigenetic analyses. The proposed facility will be the first institution capable of supporting high-throughput studies of the interactions among genes, chemicals, and diseases in the developmental context of a whole vertebrate. It will serve equally well the interests of toxicologists exploring the impact of an environmental stressor, pharmacologists developing a new drug, and geneticists wanting to identify the function and interactions of an unknown gene. The proposed high-throughput facility will serve as the Rosetta Stone of modern genomic research. It will deliver fast and inexpensive techniques for elucidating biomolecular networks in zebrafish. The research community will translate this knowledge to decipher the workings of the human genome and its interactions with the environment. PUBLIC HEALTH RELEVANCE: Research conducted at this high-throughput facility will generate mechanistic understanding of the relationships among genes, chemicals, and diseases and thereby generate useful hypotheses and targets for novel therapeutic interventions. This work will lead to better ways of preventing, treating, and curing diseases. By dramatically reducing the cost and the time required to conduct mechanistic toxicology studies, the facility will make it economically feasible to test for toxicity all of 70,000 chemicals to which commercial products expose the American public. Current procedures evaluate only about 60 chemicals a year.