Lysosomal Metabolomics and pH

溶酶体代谢组学和 pH

• 批准号: 10413973
• 负责人: Meng Carla Wang
• 金额: $ 36.11万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413973
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amino Acids; Astrocytes; Atlases; Biology of Aging; Cells; Collaborations; Coupled; Data Analyses; Disease; Disease Progression; Environment; Enzymes; Foundations; Functional disorder; Genetic; Genetic Transcription; Genotype; Goals; High Pressure Liquid Chromatography; Hippocampus (Brain); Homeostasis; Knowledge; Lasers; Libraries; Link; Longevity; Lysosomes; Mass Spectrum Analysis; Measures; Metabolic; Metabolism; Methods; Modification; Multiomic Data; Mus; Neurodegenerative Disorders; Neuroglia; Neurons; Nuclear; Organelles; Organism; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phagocytes; Photons; Physiological; Play; Process; Proteome; Protocols documentation; Quality Control; Regulation; Research; Research Project Grants; Resolution; Resources; Role; Sampling; Scanning; Series; Signal Transduction; System; Tauopathies; Techniques; Time; Wild Type Mouse; amino acid metabolism; base; cell growth; data acquisition; fluorescence lifetime imaging; genetic manipulation; healthy aging; imaging platform; in vivo monitoring; innovation; lysosomal proteins; macromolecule; mass spectrometer; metabolome; metabolomics; mouse model; nanoscope; synergism; tau Proteins; trafficking; two-photon

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.

摘要 溶酶体是高度特化和动态的细胞器，其构成细胞内的酸性环境。 细胞通过接受和降解来自分泌，内吞， 自噬和吞噬细胞运输途径。与此同时，溶酶体作为信号中心， 细胞，溶酶体的代谢状态积极调节核转录，以控制各种细胞 活动，如细胞生长，代谢和质量控制。溶酶体活性的失调已经被 与衰老和年龄相关疾病（包括阿尔茨海默病（AD））相关。溶酶体 代谢组学和pH核心（核心C）将支持PPG提案中的三个研究项目，以评估 通过利用高通量、高通量的能量， 基于质谱（MS）的代谢组学和高分辨率荧光寿命成像 显微镜（FLIM）。我们将1）在衰老和tau蛋白病小鼠中进行溶酶体特异性代谢组学分析 模型，2）使用FLIM评估溶酶体pH变化。此外，Core C将同时搭载技术和 通过开发新的技术平台和创建一流的老龄化概念创新-和 小鼠皮质溶酶体蛋白质组和代谢组的Tau病相关溶酶体图谱（ATLas） 以及海马与核心A和核心B的协作。总之，这些研究将推动我们目前的 关于溶酶体功能与衰老和AD tau蛋白病之间的关联的知识，并提供 为溶酶体生物学、衰老生物学和AD等领域提供了强大的技术和宝贵的资源 病理