HTS to discover drugs effecting protein folding in the endoplasmic reticulum

描述（由申请人提供）：我们的实验室研究了一种机制，所有人类细胞都使用这种机制来确保组装蛋白质所需的分子组分供应充足。这种机制被称为未折叠蛋白质反应（缩写为UPR）。我们正在了解到，普遍定期审议的不足或过度都可能导致重大疾病。这是因为UPR必须与细胞的需求精确匹配：当细胞被迫过度生产某些蛋白质时，太少的组装组件会导致细胞受损。这可以解释为什么胰岛β细胞（产生激素胰岛素）在肥胖个体中被迫过度产生胰岛素时会受损并死亡（从而导致2型糖尿病）。另一方面，高度活跃的UPR可能会使癌细胞在不利的条件下继续生长，否则会杀死它们。因此，重新调整UPR的能力，无论是“向上”还是“向下”，都可以用作治疗各种人类疾病如2型糖尿病或某些癌症的治疗策略。我们建议通过在定义明确的化学物质组（这些被称为化学库）中搜索来发现允许这种调节的药物。我们已经设计了一个策略，这种搜索（称为高通量筛选），依赖于我们对UPR生物化学的详细了解。这一策略的主要特点是我们发明了一种生化筛选程序，我们将利用它来筛选并从数十万种化学物质中找到我们认为有用的化学物质来调节UPR。我们希望，我们发现的化学物质将被进一步精制并开发成药物，用于测试UPR缺陷引起的疾病（如2型糖尿病和某些癌症）的治疗益处。

DESCRIPTION (provided by applicant): Our lab studies a mechanism that all human cells use to ensure that the molecular components needed to assemble proteins are in ample supply. This mechanism is called the unfolded protein response (it is abbreviated UPR). We are learning that both deficiencies or excesses in the UPR can lead to important diseases. This is because the UPR must be matched precisely to cellular need: too few assembly components will cause cells to become damaged when they are forced to overproduce certain proteins. This may explain why pancreatic islet beta cells (which produce the hormone insulin) become damaged and die when they are forced to overproduce insulin in obese individuals (consequently leading to type 2 diabetes). On the other hand, a highly vigorous UPR may allow cancer cells to continue growing under adverse conditions that would otherwise kill them. Therefore, the ability to readjust the UPR, both "up" or "down", could be useful as a therapeutic strategy to treat various human diseases such as type 2 diabetes or certain cancers. We propose to discover drugs that allow such adjustment by searching for them in well defined sets of chemicals (these are called chemical libraries). We have a devised a strategy for this search (called a high throughput screen) that relies on our detailed understanding of the biochemistry of the UPR. The main feature of this strategy is a biochemical screening procedure we have invented that we will employ to sift through and find what we think will be a few useful chemicals to modulate the UPR from very large sets of several hundred thousand chemicals. Our hope is that the chemicals we find will be further refined and developed into drugs to be tested for therapeutic benefit in diseases proceeding from defects in the UPR such as type 2 diabetes and certain cancers.