A Systematic RNAi-based Map of C. elegans Embryogenesis

基于 RNAi 的系统性线虫胚胎发生图谱

基本信息

批准号：
7527944
负责人：
KRISTIN C GUNSALUS
金额：
$ 57.4万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7527944
关键词：
Address Affect Alleles Architecture Archives Area Award Biological Biological Assay Biological Process Biology Budgets Buffers C. elegans genome Caenorhabditis elegans Cell Polarity Cell division Chromosome Mapping Classification Code Complex Data Data Analyses Data Collection Databases Development Developmental Process Disease Educational process of instructing Embryo Embryonic Development Enhancers Ensure Event Evolution Fertilization Funding Genes Genetic Genetic Models Genetic screening method Genome Goals Human Human Genome Image Kinetochores Laboratories Lead Link Maps Meiosis Mitosis Modeling Molecular Molecular Genetics Nuclear Envelope Organism Outcome Pathway interactions Pattern Phenotype Play Process Program Development Property Proteins RNA Interference Resolution Role Staging System Testing Time Work Yeasts base combinatorial data integration experience functional genomics gene interaction genetic analysis genome sequencing genome-wide human disease in vivo insight programs protein protein interaction scaffold tool

项目摘要

DESCRIPTION (provided by applicant): The early C. elegans embryo is a powerful model to study the global genetic architecture underlying development. During the current funding period we have (1) identified most of the genes required for all visible processes during early embryonic development using large-scale RNAi followed by analysis of time-lapse recordings; (2) built a global view of the molecular complexes required for early embryogenesis by integrating high-resolution phenotypes with other functional genomic data; and (3) explored the properties of the map by studying the function of several new proteins. For example, we have found that MEL-28 plays an essential role coordinating nuclear envelope and kinetochore functions in the early embryo. In the current proposal we aim to extend these studies to identify the role of proteins beyond the essential ones and to identify how the essential complexes are coordinated and functionally linked with one other. We have developed a high-throughput system for genome-wide RNAi to identify suppressor and enhancer interactions using existing conditional alleles. Using ~30 alleles of representative genes from diverse processes in the early embryo, we aim to apply this approach to build a global scaffold of suppressor and enhancer interactions in the early embryo. We expect that the identification and analysis of these genetic interactions will extend dramatically our view of the genes working in the early embryo and how they interact to coordinate biological processes. Elucidating these mechanisms will help further our understanding of complex phenotypes underlying human disease. A fundamental question, now that the human genome sequence has been elucidated, is to understand how it directs complex biological and development programs in both normal and disease states. Over the last few years we have made progress in deciphering the single gene requirements in many basic developmental processes but we have a very limited view of how multi-gene interactions affect these programs. Since most human diseases arise from complex effects of multiple interacting components it is imperative that we gain insights into these mechanisms. We will conduct genome-wide analyses to uncover genetic interactions required during the early developmental programs in the genetic model C. elegans. The resulting map will help us understand complex genetic networks underlying development and disease in humans.

描述（由申请人提供）：早期的秀丽隐杆线虫胚胎是研究全球遗传建筑基础发展的强大模型。在当前的资金期间，我们（1）使用大规模RNAi确定了早期胚胎发育过程中所有可见过程所需的大多数基因，然后分析了延时记录；（2）通过将高分辨率表型与其他功能基因组数据整合在一起，建立了早期胚胎发生所需的分子复合物的全球视图；（3）通过研究几种新蛋白的功能来探索地图的性质。例如，我们发现MEL-28在早期胚胎中的核包膜和动力学函数扮演着重要的作用。在当前的建议中，我们旨在扩展这些研究，以确定蛋白质以外的蛋白质的作用，并确定基本复合物如何协调并在功能上与一个彼此联系。我们已经开发了一个针对全基因组RNAi的高通量系统，以使用现有的条件等位基因识别抑制剂和增强剂相互作用。我们使用早期胚胎中不同过程的代表性基因的30个等位基因，我们旨在应用这种方法来在早期胚胎中建立全球抑制剂和增强子相互作用的脚手架。我们预计，对这些遗传相互作用的识别和分析将极大地扩展我们对早期胚胎中工作基因的看法，以及它们如何与坐标生物学过程相互作用。阐明这些机制将有助于我们进一步理解人类疾病的复杂表型。现在已经阐明了人类基因组序列，一个基本问题是了解它如何指导正常和疾病状态的复杂生物学和发展计划。在过去的几年中，我们在许多基本发展过程中解释单个基因需求方面取得了进展，但是我们对多基因相互作用如何影响这些程序的看法非常有限。由于大多数人类疾病是由多个相互作用成分的复杂作用引起的，因此我们必须了解这些机制。我们将进行全基因组分析，以揭示遗传模型秀丽隐杆线虫早期发育计划中所需的遗传相互作用。由此产生的地图将有助于我们了解人类发展和疾病的基本遗传网络。