Probe Development for Bromodomains Networks

 描述(由申请人提供)：基因表达的表观遗传调控是一个高度动态和可逆的过程，对正常的细胞功能至关重要。然而，它也会导致人类疾病，如癌症和炎症。参与表观遗传调控的蛋白质家族包括共价修饰染色质的编写体、识别染色质修饰的阅读器和去除修饰的擦除器。在过去的十年中，该领域的大量研究表明，许多表观遗传蛋白是潜在的可药物靶点。溴域属于读者的范畴，它识别组蛋白和其他蛋白质上的乙酰化赖氨酸残基。最近发现了几种有效的、选择性的和细胞活性的溴域化合物，这增加了人们对该家族的功能重要性和治疗潜力的认识。然而，研究是有限的，而且只集中在少数几个溴结构域亚家族，如溴结构域和外源(BET)蛋白。这些研究没有扩展到更多的阅读器蛋白有很多原因；关键的限制是产品的可用性和这些非BET亚家族靶标的知识体系。作为拟议项目的一部分，我们将系统地开发1)完整、高质量的溴结构域蛋白质，2)每个靶标的底物知识，3)每个靶标的多种检测格式，4)每个靶标的探针(S)，5)易于使用的检测试剂盒，6)新产生的阅读器结构域的检测服务，以及7)第一个药物-溴结构域相互作用数据库，我们将通过在临床试验中测试每个溴结构域与FDA批准的大量药物和制剂来建立该数据库，以提供这些常用药物和化学品如何影响与人类健康相关的表观遗传活动的信息。

 DESCRIPTION (provided by applicant): Epigenetic regulation of gene expression is a highly dynamic and reversible process essential to normal cellular function. However, it also contributes to human diseases, such as cancer and inflammation. Protein families that participate in epigenetic regulation include writers, which covalently modify chromatin; readers, which recognize chromatin modifications; and erasers, which remove modifications. A large volume of research in the field over the past decade has shown that many epigenetic proteins are potential druggable targets. Bromodomains, which belong to the reader's category, recognize acetylated lysine residues on histones and other proteins. Several potent, selective and cellularly active bromodomain compounds have recently been identified, increasing appreciation of the functional importance and therapeutic potential of this family. However, studies are limited and focus only on a few bromodomain subfamilies, such as the bromodomain and extraterminal (BET) proteins. There are a number of reasons that the studies have not expanded into more reader proteins; the key limitations are in both the availabilities of products and the body of knowledge for these non-BET subfamily targets. As part of the proposed project, we will systematically develop 1) complete, high-quality bromodomain proteins, 2) substrate knowledge for each target, 3) multiple assay formats for each target, 4) probe(s) for each target, 5) easy-to-use assay kits, 6) assay services for newly produced reader domains, and importantly, 7) the first drug-bromodomain interaction database, which we will build by testing each bromodomain against a large number of FDA-approved drugs and agents in clinical trials, to provide information on how these commonly used drugs and chemicals affect epigenetic activities relevant to human health.