Monitoring the aging lung using genomics, proteomics and informatics

利用基因组学、蛋白质组学和信息学监测肺部老化

• 批准号: 10620762
• 负责人: Alexander Misharin
• 金额: $ 37.07万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620762
• 关键词: Acceleration; Aging; Alveolar Macrophages; Animals; Award; Biological; Biology; Biology of Aging; Brain; Cell Separation; Cell physiology; Cells; Collection; Complex; Coupled; DNA; Data; Data Set; Dimensions; Disease; Electronics; Environment; Flow Cytometry; Funding; Funding Opportunities; Genetic; Genetic study; Genomics; Genotype; Health; Human; Impairment; Infection; Influenza A virus; Informatics; Injury; Instruction; Intervention; Link; Longevity; Lung; Lung diseases; Machine Learning; Macrophage; Mass Spectrum Analysis; Membrane; Metabolism; Metformin; Methods; Microglia; Mitochondria; Modeling; Monitor; Mus; Muscle; Muscle satellite cell; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology Study; Phenotype; Pneumonia; Population; Protein Biosynthesis; Proteins; Proteome; Proteomics; Protocols documentation; Publishing; RNA; Recovery; Research; Research Personnel; Sampling; Science; Signal Transduction; Skeletal Muscle; Sorting; Stress; Structure of parenchyma of lung; System; Technology; Tissue Harvesting; Tissues; aged; alveolar type II cell; biological adaptation to stress; brain tissue; data integration; healthspan; injury recovery; lung health; lung repair; mouse model; multiple omics; novel; pharmacologic; protein complex; protein folding; proteostasis; repaired; response; single-cell RNA sequencing; skeletal tissue; tissue injury; tissue mapping; tool; transcriptome sequencing; transcriptomics

ABSTRACT_CORE B The long-term health of the lung and other tissues is inextricably linked to the sustainability of the protein fold and its function. Fold and function are tightly coupled to the energetic health of the cell. This is achieved by the emerging paradigm of harmonization of cell function (DNA, RNA and protein) with protein homeostasis or proteostasis, a collection of integrated biological pathways that generate, maintain and repair the proteome. Efforts in the previous funding period revealed the importance of both proteostasis sensitive pathways and the mitochondria in management of the aging lung, pathways that are responsive to the life-span extending drug metformin that is thought to impact the function of mitochondrial complex I, and ISRIB, which our preliminary data suggests accelerates lung repair in a variety of injury models. In Core B, we will quantitatively track changes in proteostasis during recovery from influenza A-induced tissue injury using integrated bulk and single cell RNA-Seq, spatial transcriptomics and rigorous mass spectrometry (MS) approaches. We will apply these approaches to high quality flow cytometry sorted samples of lung, skeletal muscle and brain tissue from aged mice provided by Core C. Our computational groups at Northwestern and Scripps Research interact freely via shared electronic platforms. They will use these data to create a multi- dimensional understanding of the impaired recovery from influenza A infection in older animals. Core B will couple these powerful technologies with the genetic and pharmacologic studies the investigators propose to manipulate mitochondrial complex I function, the integrated stress response and ATF4 over the lifespan. We will support these important studies in aging biology by focusing on three Specific Aims: Aim 1: To provide bulk and single cell RNA-Seq and spatial transcriptomic data using flow-sorted cell populations and homogenized tissues provided by Core C. Aim 2: To provide mass spectroscopy analyses from flow-sorted cell populations obtained from the lung, brain and skeletal muscle of aged animals. Aim 3. To use advanced machine learning and system science tools to couple genetic and pharmacologic interventions during aging with multi-omic experimental data from aging animals. While the methods employed in this Core are inherently unbiased, we take advantage of the special expertise within this Core and the PPG to focus on proteostasis, macrophage biology and metabolism over the lifespan. By providing simultaneous RNA-Seq and proteomic analysis of alveolar type II cells, alveolar macrophages, Core B we will create a multi-omic genotype to phenotype map of tissue recovery after injury during aging that will be broadly applicable to other environmental challenges that limit healthspan.

Abstract_core b 肺和其他组织的长期健康与蛋白质折叠的可持续性密不可分 及其功能。折叠和功能紧密耦合到细胞的能量健康。这是由 与蛋白质稳态或 Proteostasis是一组综合生物途径，生成，维持和修复蛋白质组。 在上一个资金期间的努力揭示了蛋白质的敏感途径和 线粒体在衰老肺管理中 二甲双胍被认为会影响线粒体复合物I和Isrib的功能，这是我们的初步 数据表明，各种损伤模型中的肺修复加速。 在核心B中，我们将在从流感A诱导的组织中恢复过程中定量跟踪蛋白质的变化 使用集成的散装和单细胞RNA-seq，空间转录组学和严格的质谱法损伤 （MS）方法。我们将把这些方法应用于高质量的流式细胞仪排序的肺，骨骼样本 由CoreC提供的老年小鼠的肌肉和脑组织 Scripps研究通过共享电子平台自由互动。他们将使用这些数据来创建一个多 对年龄较大动物中流感A感染的恢复受损的尺寸理解。核心核心 将这些强大的技术与遗传学和药理学研究相结合，研究人员建议 操纵线粒体复合物I功能，整个寿命中的集成应力响应和ATF4。我们将 通过关注三个特定目的： AIM 1：使用流量排序提供散装和单细胞RNA-seq和空间转录组数据 细胞群体和由CoreC提供的均质组织。 目的2：提供从获得的流程细胞种群的质谱分析 老年动物的肺，大脑和骨骼肌。 目的3。使用先进的机器学习和系统科学工具来对遗传和 衰老期间使用来自衰老动物的多矩实验数据的药理干预措施。 虽然该核心中使用的方法本质上是公正的，但我们利用了特殊的专业知识 在该核心和PPG中，专注于蛋白质的生物学，巨噬细胞生物学和代谢。 通过提供牙槽II型细胞的同时RNA-seq和蛋白质组学分析，肺泡巨噬细胞， 核心B我们将创建一个多摩尼克的基因型，以在衰老期间受伤后组织恢复的表型图 将广泛适用于限制HealthSpan的其他环境挑战。