CHEMICAL GENETIC APPROACHES TO BASIC CELL BIOLOGY

我们计划的目的是开发一种新的方法来发现生物学、化学遗传学中的分子机制，并改变形状；以及囊泡运输，研究细胞如何在不同的隔室选择性地输入和输出蛋白质。对于这两个生物领域，化学工具尤其重要，因为我们希望研究的事件在几秒钟或几分钟内发生，而大多数其他研究方法都很慢。化学遗传学方法旨在模仿经典遗传学作为一种发现工具，通过使用改变特定蛋白质功能的化学物质来理解这些蛋白质的功能。特别是，我们希望使用化学物质来识别新的蛋白质，这些蛋白质在细胞骨架的功能或囊泡运输中并不重要。因此，我们计划积累大量的化学物质(化学库)，并使用高通量筛选来识别干扰这些过程的化学物质，然后才能识别这些化学物质结合的蛋白质。同时，我们将筛选活性化学物质的抑制剂，与整个科学界分享。在项目1和2中，我们将发现抑制细胞迁移的化学物质，以及与细胞骨架的形成和功能有关的几种关键蛋白质。在项目3中，我们将确定新的进入和出站小泡流量的抑制剂。在项目4中，我们将开发新的方法来确定这些化学品的目标，并开发新的方法来评估化学库对生物筛选的有用性。在项目5中，我们将构建一个仿照生物碱的化学库，我们预计生物碱将成为生物活性化学物质的丰富来源。三个核心将支持这项工作：核心A将提供行政支持，核心B将使该计划的筛选和数据库功能成为可能，核心C将支持所有具有合成化学专业知识的项目。

The aim of our program is to develop a novel approach to discovering molecular mechanism in biology, chemical genetics, and to change shape; and vesicle trafficking, the study of how cells selectively import and export proteins in different compartments. For both of these biological areas, chemical tools are particularly important because the events we wish to study happen in seconds or minutes, and most other methods of study are slow. The chemical genetics approach aims to emulate classical genetics as a discovery tool, by using chemicals that alter the functions of specific proteins as a way to understand the functions of these proteins. In particular, we want to use chemicals to identify new proteins, not previously known to be important in the function of the cytoskeleton or in vesicle trafficking. We therefore plan to accumulate large collections of chemicals (chemical libraries) and use high-throughput screening to identify chemicals that interfere with these processes, and only then identify the proteins that the chemicals bind to. In parallel, we will screen for inhibitors of active chemicals to share with the whole scientific community. In Projects 1 and 2, we will discover chemicals that inhibit cell migration and several key proteins involved in formation and function of the cytoskeleton. In Project 3, we will identify novel inhibitors of in-bound and out-bound vesicle traffic. In Project 4, we will develop new methods for identifying the targets of those chemicals, and new ways to assess the usefulness of a chemical library for biological screening. In Project 5, we will construct a chemical library patterned after alkaloids, which we expect to be a rich source of biologically active chemicals. Three Cores will support this work: Core A will provide administrative support, Core B will make the screening and database functions of the Program possible, and Core C will support all projects with synthetic chemistry expertise.