Connectivity Map 100k

项目概述：Connectivity Map 100k项目旨在建立一个综合的“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。这样的连接图将使世界各地的研究人员能够产生可测试的假设，否则这些假设可能仍未被发现。通过使用基因组特征作为描述不同细胞状态的通用语言，广泛的研究应用将成为可能。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谱，这将服务于两个重要目的。首先，它将生成一个扩展的连接地图数据库，这将进一步支持生物发现。其次，它将为未来更大规模的连通性地图资源建立参数，例如，可能包括所有人类和小鼠基因的扰动概况以及大量细胞类型中的数十万小分子。在目标1中，我们将把我们的试点药理学连通性图数据扩展到遗传扰动。具体来说，我们将使用慢病毒shrna来降低10种不同细胞类型中1000个人类基因的表达。这些实验将建立开发大规模遗传扰动特征的可行性，并将建立观察到的连接的细胞上下文依赖程度。在目标2中，我们将在10种不同的细胞类型中生成1500种小分子（fda批准的药物和工具化合物的混合物，正在nih资助的化学生物学项目中进行研究）的概况。在这个为期两年的项目结束时，我们期望a)生成100,000个微扰资料，并通过用户友好的网络界面公开访问，b)为创建未来的、基于社区的、大规模的连接地图公共资源奠定基础。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。它有可能产生基因组功能注释的新方法，为阐明小分子化合物的作用机制提供一条途径，并促进发现对疾病生物学具有意想不到的治疗作用的药物。

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.