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.

人们通常每个基因都有两个拷贝。人类拥有的众多疾病相关基因之一的突变会增加患疾病的风险。但这些与疾病相关的基因之一发生突变并不总是意味着一个人就会患上这种疾病。这种情况已知发生在帕金森病 (PD) 中，其中导致 PD 的最常见遗传因素是 GBA 基因突变。该基因编码蛋白质葡萄糖脑苷脂酶（GCase），该酶将葡萄糖从糖修饰的脂肪分子中切断，这种脂肪分子在大脑中特别丰富。尽管携带这种突变的人更有可能更早患帕金森病并且症状更严重，但并非所有携带 GBA 基因突变的人都会患帕金森病。这导致人们猜测还有其他基因与 GBA 相互作用，从而增加或减少患帕金森病的几率。已知这种情况也会发生在其他疾病中，其中各种基因的突变可以通过所谓的遗传相互作用影响患特定疾病的可能性。因此，人们对鉴定与 GBA 相互作用的基因以及了解它们如何影响 GCase 功能产生了浓厚的兴趣。事实上，人们对 GCase 在细胞内如何调节知之甚少，但这些基本信息可以帮助更好地理解这种蛋白质的调节。在本提案中，我们的目标是利用我们在化学生物学工具方面的最新进展，能够直接观察活细胞中 GCase 蛋白的活性。此外，我们将化学合成新的探针分子，能够以新的方式测量这种酶的活性。最终，我们将使用这些化学工具通过最先进的筛选方法来识别与 GBA 相互作用的基因。这样我们就能基本了解这些基因如何调控GCase。制药公司可以利用这些知识来创造新药，使加拿大和世界各地的帕金森病患者受益。由于帕金森病是第二常见的神经退行性疾病，并且没有任何治疗方法可以减缓帕金森病的进展，因此非常需要新的见解来创造新的药物。