Chemical biology probes to monitor glucocerebrosidase activity in fixed cells and tissues

用于监测固定细胞和组织中葡萄糖脑苷脂酶活性的化学生物学探针

• 批准号: 558261-2020
• 负责人: Vocadlo, David
• 金额: $ 4.27万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=721674
• 关键词: Chemical; biology; probes; monitor; glucocerebrosidase

People generally have two copies of each gene. A mutation in one of the many disease-related genes that humans have can increase the risk of developing disease. But having a mutation in one of these disease-related genes does not always mean that a person will get the disease. Such a case is known to occur in Parkinson Disease (PD) where the most common hereditary factor contributing to PD are mutations in the gene called GBA. This gene codes for the protein glucocerebrosidase (GCase) that cuts glucose off from a sugar-modified fat molecule that is especially abundant in brain. Even though people with this mutation are much more likely to get PD earlier on and have more severe symptoms, not all people who have a mutation in the GBA gene do develop PD. This has led people to hypothesize that there are other genes that interact with GBA and either increase or decrease the chance of getting PD. This is known to occur for other diseases where mutations in various genes can influence the likelihood of developing a specific disease through what is known as a genetic interaction. There is accordingly high interest in identifying genes that interact with GBA and then understanding how they might influence GCase function. Indeed, little is known about how GCase is regulated within cells but such fundamental information could help better understand the regulation of this protein. In this proposal we aim to exploit our recent advances in chemical biology tools that enable directly watching the activity of GCase protein in living cells. In addition, we will chemically synthesize new probe molecules that enable measuring the activity of this enzyme in new ways. Ultimately, we will use these chemical tools to identify genes that interact with GBA using state of the art screening methods. In this way we will get a basic understanding of how such genes could regulate GCase. Such knowledge could be exploited by pharmaceutical companies to create new drugs that could benefit PD patients in Canada and around the world. Because PD is the second most common neurodegenerative disease, and there is no treatment that slows progression of PD, there is a great need to new insights that could be exploited to create new medicines.

人们通常有每个基因的两个副本。人类拥有的许多与疾病相关的基因之一的突变可以增加患疾病的风险。但是，在这些与疾病相关的基因之一中有突变并不总是意味着一个人会患上这种疾病。已知这种情况发生在帕金森氏病（PD）中，其中最常见的遗传因子是PD的最常见因素是该基因中的突变，称为GBA。该基因编码蛋白质葡萄糖脑溴糖苷酶（GCASE），该蛋白质从大脑中特别丰富的糖改性脂肪分子中切掉葡萄糖。即使患有这种突变的人更有可能较早地恢复PD并具有更严重的症状，但并非所有在GBA基因中都有突变的人都会发展为PD。这使人们假设还有其他基因与GBA相互作用，并增加或减少获得PD的机会。已知这是其他疾病发生的，在其他疾病中，各种基因的突变会影响通过所谓的遗传相互作用发展特定疾病的可能性。因此，识别与GBA相互作用的基因，然后了解它们如何影响GCASE功能的兴趣很高。实际上，关于GCASE如何在细胞中调节的知之甚少，但是这种基本信息可以帮助更好地理解该蛋白的调节。在此提案中，我们旨在利用我们在化学生物学工具方面的最新进展，这些工具可以直接观察GCASE蛋白在活细胞中的活性。此外，我们还将化学合成新的探针分子，该分子能够以新的方式测量该酶的活性。最终，我们将使用这些化学工具使用最先进的筛选方法来识别与GBA相互作用的基因。通过这种方式，我们将对这种基因如何调节GCASE有一个基本的了解。制药公司可以利用这种知识来创建可以使加拿大和世界各地PD患者受益的新药。由于PD是第二个常见的神经退行性疾病，并且没有治疗方法可以放慢PD的进展，因此非常需要进行新的见解，这些见解可以被利用来创建新药物。