Technology to Identify and Assay Chemical Genomic Probes

描述（由申请人提供）：本提案的主要目的是开发和部署尖端技术和化学基因组工具，了解小分子抑制剂在体内的作用，并在系统水平上表征模式生物酿酒酵母。在过去的3.5年中，作为NHGRI资助项目的一部分，我们已经将三种独特的全基因组筛选应用于约2，000种化学生长抑制剂。这些数据导致了几个值得注意的发现，包括：1）新的药物/靶标相互作用，2）几乎所有酵母基因的化学表型，3）酵母的系统水平表征，以及4）更好地理解化学结构-活性关系，因为它们在体内表现出来。这些数据还指导了本文提出的下一代化学基因组测定的设计。利用我们已建立的生物信息学和机器人基础设施，我们将设计下一代检测方法，以前所未有的严格程度来询问基因组与小分子的相互作用，同时降低每种化学品的成本。公共卫生相关性：小分子，这一提案的中心焦点，构成了FDA批准的大多数药物。不幸的是，制药行业目前正在经历飞涨的成本（每种新药约8亿美元）以及稳步下降的生产率。这些困难部分归因于有前途的候选药物的不可预见的副作用，以及缺乏药物可以结合并产生药效的有效细胞“靶点”。本提案的具体目标是解决这两个问题。

DESCRIPTION (provided by applicant): The primary objective of this proposal is to develop and deploy cutting edge technologies and chemical genomic tools and to understand the effects of small molecule inhibitors in vivo, and to characterize the model organism Saccharomyces cerevisiae on a systems level. Over the course of the past 3.5 years, as part of an NHGRI-funded project, we have applied three unique genome-wide screens to ~2,000 chemical inhibitors of growth. These data have led to several notable findings, including: 1) novel drug/target interactions, 2) a chemical phenotype for nearly all yeast genes, 3) a systems-level characterization of yeast, and 4) a better understanding of chemical structure-activity relationships as they manifest in vivo. These data have also guided the design of the next-generation chemical genomic assays proposed herein. Using our established bioinformatics and robotics infrastructure, we will design the next generation of assays to interrogate the genome's interaction with small molecules to unprecedented levels of scrutiny, while decreasing cost per chemical. PUBLIC HEALTH RELEVANCE: Small molecules, the central focus of this proposal, make up the majority of FDA approved drugs. Unfortunately, the pharmaceutical industry is currently experiencing sky-rocketing costs (~800 million dollars per new drug) in addition to steadily decreasing productivity. These struggles are attributed in part to unforeseen side-effects of promising drug candidates and by a lack of validated cellular "targets" to which a drug can bind and elicit a medicinal effect. The specific aims of this proposal address both of these problems.