Investigating protein aggregation with small molecules

研究综述：哺乳动物的蛋白质种类繁多，有些蛋白质会发生错误折叠，形成聚集体。研究表明，这些部分紊乱的蛋白质聚集体可能对细胞有毒。然而，蛋白质错误折叠和聚集的确切性质仍在研究中。在我们的建议中，我们旨在通过使用小分子作为研究蛋白质聚集机制的工具来回答这些问题。小分子文库将被合成，生化研究将通过一些技术来监测蛋白质聚集动力学。这些研究将有助于在分子水平上阐明参与蛋白质聚集的关键区域。此外，这些研究将得到计算模型的支持，以确定蛋白质-小分子相互作用的性质及其在蛋白质聚集/分解中的作用。我们预计这些研究将通过阐明蛋白质聚集途径的机制来推进我们现有的知识，并将有助于开发研究蛋白质聚集的新工具。

Research Summary: Among the many and diverse proteins in mammals, some proteins can misfold and form aggregates. Studies indicate that these partially disordered protein aggregates can be toxic to cells. However the exact nature of protein misfolding and aggregation is still a work in progress. In our proposal we are aiming to answer these questions, by using small molecules as tools to study the mechanisms of protein aggregation. Small molecule libraries will be synthesized and biochemical studies will be conducted to monitor protein aggregation kinetics by a number of techniques. These studies will assist in elucidating the critical regions involved in protein aggregation at the molecular level. Furthermore, these investigations will be supported by computational modeling to determine the nature of protein-small molecule interactions and their role in protein aggregation/disaggregation. We anticipate that these studies will advance our current knowledge by elucidating the mechanisms of protein aggregation pathway and will assist in developing novel tools to study protein aggregation. HQP training: Our proposed research program will train several graduate and undergraduate students over the next five years. Students will be trained in a number of research techniques which will provide the necessary skill sets to succeed in academic or industrial settings as future scientists and contribute to the growth of scientific and economic landscape in Canada.