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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710177
• 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.

对于许多生物体来说，生存取决于对温度、氧气和水供应等环境变化的适应。在这些压力中，大多数后生动物的生存本质上与氧气的供应有关，因此已经进化出能够在环境严重减少的情况下生存的机制。对于人类来说，缺氧最常见于高海拔地区、发育过程以及中风、高血压、缺血性心脏病和急性心肌梗塞等许多临床病症。在细胞应激期间，蛋白质的可逆翻译后修饰（PTM）使细胞能够快速改变其细胞环境并调节蛋白质功能以响应各种刺激。最近探索翻译后赖氨酸 (Lys) 甲基化作用的研究表明，动态甲基化的功能与其他 PTM 类似，是快速调节蛋白质功能和生物过程的一种手段。最近已证明，涉及低氧感应和生物体生存的多种途径，包括 HIF-1（缺氧诱导因子-1）、未折叠蛋白反应以及 NFkb 和 PI3K-Akt 信号传导途径，均受到 Lys 甲基化的可逆调节然而，低氧应激下甲基化诱导的这些途径的调节之间的联系尚未被探索。尽管最近的研究表明赖氨酸甲基化是一种普遍存在的 PTM，具有多种功能作用，但我们才刚刚开始描绘甲基赖氨酸蛋白质组的范围及其可以调节的全谱细胞和发育过程。迄今为止，甲基化研究主要集中在赖氨酸甲基化蛋白和修饰位点的发现上，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，加上我在功能蛋白质组学和赖氨酸甲基化发现方面的博士后研究，使我的研究工作处于前所未有的位置，以推进对蛋白质甲基化如何调节低氧环境中生存的基本理解。我的实验室将专注于将比较应激生物学、功能蛋白质组学和生物信息学结合起来，发现并确定翻译后赖氨酸甲基化在使细胞能够在缺氧（1% O2）下生存的途径和信号网络的基本调节中的生物学意义。 我的研究贡献不仅将增强我们对低氧应激反应、蛋白质甲基化和功能的基本理解，还将发现赖氨酸甲基化蛋白质如何促进和协调对人类氧限制的最基本和危及生命的压力之一的反应。