Unravelling the mechanism of transcellular chaperone signalling in C. elegans

阿尔茨海默氏症、帕金森氏症和亨廷顿氏症等与老年人有关的疾病是我们老龄化社会面临的最大挑战之一。这些毁灭性疾病的发病有一个共同的特征，即大脑中不健康的细胞积累了变形的蛋白质，即所谓的错误折叠蛋白质。为了修复这些蛋白质并恢复健康，细胞已经进化出一种称为应激反应的保护机制，其中将产生一种称为伴侣蛋白的蛋白质家族来修复受损的蛋白质。本研究以圆线虫C. elegans已经证明了一种新的组织间通讯，它允许一个受压力的器官向其他器官中的健康细胞发出警报，指示它们产生更多的保护性伴侣。这个过程被称为跨细胞伴侣信号（TCS），也存在于哺乳动物中。目前，TCS及其与人类疾病相关机制的关键问题是寻找调节这种组织间通讯的“信使”。我们的初步观察表明，PQM-1（一种控制基因表达的蛋白质因子）和ASP-12（一种假定的分泌分子）都在TCS和应激反应中起关键作用。我们正计划了解它们在这些事件中的作用以及它们在人类疾病发病中的作用。利用C. elegans，我们将建立一个新的工具，将揭示核心分子伴侣在蠕虫所有组织的应激反应中的保护作用。我们将监测分子伴侣在正常发育过程中的表达，应激反应和TCS，以全面了解如何“跨细胞分子伴侣表达”可以发展为一种新的治疗方法来治疗蛋白质错误折叠疾病。换句话说，这意味着我们可以激活健康组织的保护性伴侣，然后向受疾病影响的组织（例如大脑）发出“信号”，以产生更多的保护性伴侣。我们的工作将产生宝贵的信息，可以指示研究人员使用啮齿动物模型来研究完整动物的应激反应。我们的方法将提供一个很好的替代工具，在C中进行试点研究。在哺乳动物实验之前，这种方法将大大减少用于这类实验的动物数量。我们的目标是了解细胞如何科普压力，以及组织如何相互交流以执行压力反应。我们团队进行的创新研究将推动边界，以寻找由错误折叠蛋白质积累引起的人类疾病的潜在治疗方法。

Age-related diseases including Alzheimer's, Parkinson's and Huntington's Disease is one of the biggest challenges for our aging society. The onset of these devastating diseases share a common feature, where unhealthy cells in the brain accumulate deformed proteins so-called misfolded proteins. To repair these proteins and restore health, cells have evolved a protective mechanism called stress responses where a family of proteins called chaperones will be produced to fix the damaged proteins. My research using the round worm nematode C. elegans has demonstrated a novel inter-tissue communication that allows a stressed organ to send out an alert to healthy cells in other organs to instruct them producing more protective chaperones. This process is called transcellular chaperone signalling (TCS) and is also found in mammals. Currently, the key question for TCS and its mechanisms relevant to human diseases is to search for the "messenger" that regulates this inter-tissue communication. Our preliminary observation showed that PQM-1 (a protein factor that controls gene expression) and ASP-12 (a putative secretory molecule) both play a key role in TCS and stress response. We are planning to understand how they function in these events and their roles in the onset of human diseases. Using C. elegans, we will build a new tool that will reveal the protective role of core chaperones in stress response across all tissues in the worms. We will monitor the chaperone expression during normal developmental processes, stress response and TCS to comprehensively understand how "transcellular chaperone expression" could be developed as a novel therapeutic approach to treat protein misfolding diseases. In other words, this means that we could activate protective chaperones from a healthy tissue which then "signals" to a tissue affected by disease (e.g. brain) to produce more protective chaperone. Our work will generate invaluable information that can be indicative to researchers using rodent models to study stress responses in an intact animal. Our approach will provide a great alternative tool to perform pilot studies in C. elegans prior the mammalian animal experiments. This approach will greatly reduce the amount of animals used in these kinds of experiments.Our aim is to understand how cells cope with stress and how tissues communicate with each other to perform stress response. The innovative research conducted in our team will push the boundary to search for potential treatments for human diseases caused by the accumulation of mis-folded proteins.