Connectivity Map 100k

描述（由申请人提供）：项目概述：连接图100 k项目旨在建立一条通往全面的“功能查找表”的道路，该表将疾病生物学，基因组功能和小分子作用联系起来。这样的连通性地图将使世界各地的研究人员能够产生可验证的假设，否则这些假设可能会被发现。通过使用基因组签名作为描述不同细胞状态的共同语言，将能够实现广泛的研究应用。我们在这里提出了一个雄心勃勃的计划，以产生100，000个遗传和药理学扰动的连接图配置文件，这将服务于两个重要目的。首先，它将生成一个扩展的连通性地图数据库，进一步支持生物发现。其次，它将为未来更大规模的连接图资源建立参数，例如，可能包括所有人类和小鼠基因以及大量细胞类型中数十万个小分子的扰动谱。在目标1中，我们将把我们的试验性药理学连接图数据扩展到遗传扰动。具体来说，我们将使用慢病毒shRNA在10种不同的细胞类型中敲低1,000个人类基因的表达。这些实验将确定开发大规模遗传扰动签名的可行性，并将确定所观察到的连接的细胞上下文依赖程度。在目标2中，我们将生成1，500种小分子（FDA批准的药物和NIH赞助的化学生物学项目正在研究的工具化合物的混合物）的概况，同样是在10种不同的细胞类型中。在这个为期2年的项目结束时，我们预计a）将生成100，000个扰动配置文件，通过用户友好的Web界面公开访问，以及B）为创建未来的基于社区的大规模连通性地图公共资源奠定基础。相关性拟议的项目预计将对广泛的生物医学研究界产生重大影响。它有可能产生新的方法来基因组功能注释，提供一条途径，阐明小分子化合物的作用机制，并促进发现药物对疾病生物学的意想不到的治疗效果。 公共卫生相关性：说明：Connectivity Map 100 k项目旨在建立一个全面的“功能查找表”，将疾病生物学，基因组功能和小分子作用联系起来。通过生成一个包含100 000个遗传和药理学扰动基因表达谱的数据库，连通图将使生物医学界能够获得一套工具，促进将疾病生物学、基因组生物学和化学生物学联系起来的系统发现。拟议的项目将为未来大规模的社区范围内的努力奠定基础，以创建一个公共连接地图资源，该资源跨越大量细胞类型的不同扰动配置文件。

DESCRIPTION (provided by applicant): PROJECT SUMMARY: The Connectivity Map 100k project aims to forge a path toward a comprehensive 'functional look-up table' that that links disease biology, genome function and small-molecule action. Such a Connectivity Map would enable researchers worldwide to generate testable hypotheses that might otherwise remain undiscovered. By using genomic signatures as a common language with which to describe different cellular states, a broad range of research applications would be enabled. We propose here an ambitious plan to generate 100,000 Connectivity Map profiles of genetic and pharmacologic perturbation that will serve two important purposes. First, it will generate an expanded Connectivity Map database that will further support biological discovery. Second, it will establish the parameters for a future, larger scale Connectivity Map resource that might include, for example, profiles of perturbation of all human and mouse genes plus hundreds of thousands of small-molecules in a large number of cell types. In Aim 1, we will extend our pilot pharmacologic Connectivity Map data to genetic perturbations. Specifically, we will use lentiviral shRNAs to knock down the expression of 1,000 human genes in 10 diverse cell types. These experiments will establish the feasibility of developing large-scale signatures of genetic perturbation, and will establish the extent of cellular context-dependence of the observed connections. In Aim 2, we will generate profiles of 1,500 small-molecules (a blend of FDA-approved drugs and tool compounds being studied in NIH-sponsored chemical biology programs), again in 10 diverse cell types. By the end of this 2-year project, we expect a) to have generated 100,000 perturbational profiles made publicly accessible via a user-friendly web interface, and b) to have laid the foundation for the creation of a future, community-based, large-scale Connectivity Map public resource. RELEVANCE The proposed project is expected to have significant impact on a broad range of the biomedical research community. It has the potential to yield new approaches to genome functional annotation, to provide a path toward the elucidation of mechanism-of-action of small-molecule compounds, and to facilitate the discovery of drugs with unanticipated therapeutic effects on disease biology. PUBLIC HEALTH RELEVANCE: NARRATIVE: The Connectivity Map 100k project aims to forge a path toward a comprehensive 'functional look-up table' that links disease biology, genome function and small-molecule action. Through the generation of a database of 100,000 gene expression profiles of genetic and pharmacologic perturbation, the Connectivity Map will enable the biomedical community with a set of tools that facilitate systematic discoveries that link disease biology, genome biology and chemical biology. The proposed project will lay the groundwork for a future, large-scale, community-wide effort to create a public Connectivity Map resource that spans diverse perturbational profiles across a large number of cell types.