Discovery and functional characterization of the hypoxia-responsive methyllysine proteome

缺氧反应甲基赖氨酸蛋白质组的发现和功能表征

• 批准号: RGPIN-2016-06151
• 负责人: Biggar, Kyle
• 金额: $ 2.77万
• 依托单位: Carleton University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744288
• 关键词: Discovery; functional; characterization; hypoxia; responsive

For many organisms, survival is dependent upon adapting to environmental variability in temperature, oxygen, and water supply. Among these stresses, survival of most metazoans is inherently tied to the availability of oxygen, such that mechanisms have evolved to survive severe reductions in the environment. In humans, oxygen restriction is most commonly encountered at high altitudes, during development, and in many clinical conditions such as stroke, hypertension, ischemic heart disease, and acute myocardial infarction. During periods of cell stress, the reversible post translational modification (PTM) of proteins provide cells with the ability to rapidly modify their cellular environment and regulate protein function in response to various stimuli. Recent research exploring the role of post translational lysine (Lys) methylation has shown that dynamic methylation functions in a similar manner to other PTMs, as a means to rapidly regulate protein function and biological processes. Several pathways involved in low oxygen sensing and organismal survival, including HIF-1 (hypoxia-inducible factor-1), the unfolded protein response, as well as NFkb and PI3K-Akt signaling pathways have been recently documented to undergo reversible regulation by Lys methylation, however the link between methylation-induced regulation of these pathways under low oxygen stress have not yet been explored. Although studies have recently established that Lys methylation is a prevalent PTM with diverse functional roles, we have only just begun to delineate the extent of the methyllysine proteome and the full spectrum of cellular and developmental processes that it can regulate. To date, methylation research has been primarily focused on the discovery of Lys methylated protein and modification sites, with little knowledge of its biological consequence. My research expertise in low oxygen biology, paired with my postdoctoral research in functional proteomics and Lys methylation discovery, place my research effort in an unprecedented position to advance the basic understanding of how protein methylation regulates survival in low oxygen environments. My lab will focus on bringing together comparative stress biology, functional proteomics, and bioinformatics to discover and assign biological significance to post translational Lys methylation in the fundamental regulation of pathways and signaling networks that enable cells to survive hypoxia (1% O2).My research contributions will not only empower our basic understanding of low oxygen stress response, protein methylation, and function, but will also discover how Lys methylated proteins contribute and coordinate the response to one of the most fundamental and life-threatening stresses to humans oxygen limitation.

对于许多生物，生存取决于适应温度，氧气和供水的环境变化。在这些压力中，大多数后生动物的存活与氧气的可利用性固有息息相关，因此机制已进化为在环境中的严重降低中生存。在人类中，氧气限制最常见于高海拔，发育期间以及许多临床状况，例如中风，高血压，缺血性心脏病和急性心肌梗死。在细胞应激期间，蛋白质的可逆后翻译后修饰（PTM）提供了能够快速修饰其细胞环境并响应各种刺激而调节蛋白质功能的能力。最近的研究探讨了转化后赖氨酸（LYS）甲基化的作用，表明动态甲基化的功能与其他PTM相似，作为快速调节蛋白质功能和生物过程的手段。最近已经记录了几种参与低氧气传感和生物生存的途径，包括HIF-1（缺氧诱导因子1），展开的蛋白质反应以及NFKB和PI3K-AKT信号传导途径已被记录在以下，以通过裂解甲基化来接受可逆调节但是，尚未探索甲基化引起的这些途径在低氧气应激下的调节之间的联系。尽管研究最近确定LYS甲基化是具有多种功能作用的普遍PTM，但我们才刚刚开始描述甲基透析蛋白蛋白质组的程度以及可以调节的整个细胞和发育过程。迄今为止，甲基化研究主要集中在发现Lys甲基化蛋白质和修饰位点的发现，对其生物学后果知之甚少。我在低氧生物学方面的研究专业知识与我在功能蛋白质组学和LYS甲基化发现方面的博士后研究相吻合，将我的研究工作置于前所未有的位置，以促进对蛋白甲基化如何调节低氧环境中蛋白质甲基化的基本了解。我的实验室将着重于将比较应激生物学，功能蛋白质组学和生物信息学结合在一起，以发现和分配生物学意义，以在途径和信号网络的基本调节中，以使细胞能够生存下降的途径和信号网络中。贡献不仅将赋予我们对低氧应激反应，蛋白甲基化和功能的基本理解，而且还将发现LYS甲基化蛋白如何贡献和协调对对人类氧气限制最基本和生命的胁迫之一的反应。