HTS to discover drugs effecting protein folding in the endoplasmic reticulum

描述(申请人提供)：我们的实验室研究一种所有人类细胞都使用的机制，以确保组装蛋白质所需的分子成分有充足的供应。这种机制被称为未折叠蛋白质反应(简称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要的疾病。这是因为UPR必须与细胞需求精确匹配：当细胞被迫过度生产某些蛋白质时，太少的组装组件将导致细胞受损。这可能解释了为什么当肥胖者被迫过度分泌胰岛素(从而导致2型糖尿病)时，胰岛β细胞(产生胰岛素的细胞)会受损并死亡。另一方面，高度活跃的UPR可能会允许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”，都可能作为一种治疗策略用于治疗各种人类疾病，如2型糖尿病或某些癌症。我们建议通过在定义明确的化学物质(称为化学库)中进行搜索来发现允许这种调节的药物。我们为这种搜索设计了一种策略(称为高通量筛选)，这依赖于我们对UPR生物化学的详细了解。这一策略的主要特点是我们发明的生化筛选程序，我们将利用该程序从数十万种化学物质的非常大的集合中筛选并找到我们认为将是调节UPR的几种有用的化学物质。我们希望，我们发现的化学物质将被进一步提炼并开发成药物，用于测试因UPR缺陷而产生的疾病的治疗效果，如2型糖尿病和某些癌症。

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.