Lysosomal Metabolomics and pH

摘要 溶酶体是高度专业化和动态的细胞器，它构成了一个酸性的环境。 细胞通过接收和降解来自分泌、内吞、 自噬和吞噬运输途径。同时，溶酶体起着信号中枢的作用。 细胞，而溶酶体的代谢状态积极地调节核转录，以调控各种细胞 活动，如细胞生长、新陈代谢和质量控制。溶酶体活性的错误调节一直是 与衰老和年龄相关疾病有关，包括阿尔茨海默病(AD)。《溶酶体》 代谢组学和pH核心(核心C)将支持本PPG提案中的三个研究项目，以评估 利用高通量、高通量、高活性的溶酶体pH和代谢活性的变化 基于精确质谱学的代谢组学和高分辨率荧光寿命成像 显微镜(薄膜)。我们将1)在衰老和自闭症小鼠中进行溶酶体特异性代谢组谱分析 模型，2)用FLIM评估溶酶体的pH变化。此外，核心C将搭载技术和 通过开发新技术平台和创建一流的老龄化来进行概念创新-以及 小鼠大脑皮质溶酶体蛋白质组和代谢组的共病相关溶酶体图谱(图谱) 和海马体，与核心A和核心B合作，这些研究将推动我们目前的 了解溶酶体功能与衰老和AD肌萎缩侧索硬化症的关系并提供 溶酶体生物学、衰老生物学和AD领域的强大技术和宝贵资源 病理学。

Abstract Lysosomes are highly specialized and dynamic cellular organelles, which constitute an acidic environment in the cell and are metabolic active by receiving and degrading macromolecules from the secretory, endocytic, autophagic and phagocytic trafficking pathways. At the same time, lysosomes act as the signaling center of the cell, and the metabolic status of the lysosome actively regulates nuclear transcription to govern various cellular activities, such as cell growth, metabolism and quality control. Misregulation of lysosomal activity has been associated with aging and age-associated diseases, including Alzheimer’s disease (AD). The Lysosomal Metabolomics and pH Core (Core C) will support three Research Projects in this PPG proposal to assess changes in lysosomal pH and metabolic activity through harnessing the power of high-throughput, high accuracy Mass Spectrometry (MS)-based metabolomics and high-resolution fluorescence lifetime imaging microscopy (FLIM). We will 1) perform lysosome-specific metabolomic profiling in aging and tauopathy mouse models, 2) assess lysosomal pH changes using FLIM. In addition, Core C will carry both technological and conceptual innovations by developing new technological platforms and by creating the first-in-class Aging- and Tauopathy-associated Lysosomal atlas (ATLas) of the lysosomal proteome and metabolome for mouse cortex and hippocampus in collaboration with Core A and Core B. Together, these studies will advance our current knowledge regarding the association between lysosomal functions and aging and AD tauopathy and provide powerful techniques and valuable resources to the fields of lysosomal biology, aging biology, and AD pathology.