HTS to discover drugs effecting protein folding in the endoplasmic reticulum

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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.