A Systems Biology Approach to Mapping Aging in the lung

绘制肺部衰老图谱的系统生物学方法

• 批准号: 9396984
• 负责人: Paul A Reyfman
• 金额: $ 7.53万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396984
• 关键词: Address; Adoptive Transfer; Affect; Age; Age-Months; Aging; Algorithms; Alveolar; Alveolar Macrophages; Animals; Applications Grants; Award; Biochemical Genetics; Biological; C57BL/6 Mouse; Cells; Chronic Obstructive Airway Disease; Chronology; Coupled; Data; Data Set; Development; Disease; Elderly; Epithelial Cells; Fellowship; Flow Cytometry; Fluorescence-Activated Cell Sorting; Foundations; Future; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Genomics; Genotype-Tissue Expression Project; Goals; Growth; Harvest; Homeostasis; Human; Immune; Individual; Infection; Influenza A virus; Innate Immune System; Laboratories; Laboratory mice; Lead; Learning; Linear Regressions; Longevity; Lung; Lung diseases; Malignant neoplasm of lung; Maps; Mentors; Modeling; Molecular; Morbidity - disease rate; Mus; National Research Service Awards; Pathway interactions; Physicians; Play; Population; Predisposition; Principal Component Analysis; Proteomics; Publishing; Pulmonary Fibrosis; Rattus; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Scientist; Series; Structure of parenchyma of lung; Supervision; Surface; Systems Biology; Therapeutic Intervention; Time; Tissues; Training; Virus Diseases; age related; aged; alveolar type II cell; base; career; cell type; cohort; design; disease diagnosis; educational atmosphere; forest; genomic data; insight; juvenile animal; lung development; mortality; mouse model; network models; novel; novel therapeutics; predictive modeling; prospective; skills; surfactant; targeted treatment; transcriptome sequencing; transcriptomics

PROJECT SUMMARY This proposal for an NRSA Individual Fellowship is motivated by two overarching goals: 1) to provide a rich environment for learning and growth to support the candidate's development into an effective physician- scientist, and 2) to generate a molecular map of aging in the lung by applying a systems biology approach to the analysis of transcriptomic data obtained over the lifespan of the laboratory mouse. The candidate and his mentors have designed a specific training plan that includes a rigorous research component and lays the foundation for a successful career. Aging is a key risk factor for morbidity and mortality related to diseases that affect the lung, however, the biological mechanisms contributing to this are not understood. The candidate will employ a systems biology approach to analyze already generated datasets to identify molecular pathways of aging in the lung. A better understanding of aging in the lung may ultimately lead to the development of novel therapies for lung diseases in older adults. Gene expression profiling using RNA-Seq has been used to generate “maps” of tissues by depicting tissues and purified constituent cellular populations on a molecular level. Transcriptional profiles from individuals with disease have been compared to those from healthy individuals in an attempt to develop “signatures” for a given disease. These signatures can be useful for disease diagnosis as well as for identifying targets for therapy. This proposal focuses on the contributions of two abundant cell populations in the lung, alveolar macrophages and alveolar type II cells (AT2), to the transcriptional signatures of aging in the lung. The candidate has preliminary data demonstrating evidence of an aging signature in alveolar macrophages and AT2 cells purified from mice at 18 months compared with 3 months. This signature persists during an influenza A virus infection challenge. The purpose of this proposal is to employ a systems biology approach to analyze transcriptomic data already obtained by investigators in the candidate's laboratory that includes whole lung tissue, alveolar macrophages, and AT2 cells harvested from mice over the lifespan (2 weeks, and 6,12,18 and 24 months of age). In Specific Aim 1, the candidate will generate a transcriptional map of aging in murine whole lung and purified cellular populations of alveolar macrophages and AT2 cells. In Specific Aim 2, the candidate will determine whether the transcriptional signature of aging in alveolar macrophages is cell autonomous or is driven by changes in the alveolar local microenvironment. Over the course of this award, the candidate will learn new systems biology approaches to analyzing large time-series genomic datasets and will develop a comprehensive understanding of the age-related changes in the innate immune system of the lung. The skills developed as part of this project will serve as a guide for the analysis of similar genomic data harvested from aging humans with lung disease.

项目摘要 NRSA个体奖学金的这一建议是由两个总体目标激励的：1）提供富人 学习和成长的环境，以支持候选人的发展成为有效的医生 科学家和2）通过将系统生物学方法应用于肺中的衰老分子图 在实验室小鼠的寿命中获得的转录组数据的分析。候选人和他的 导师设计了一个特定的培训计划，其中包括严格的研究组成部分，并放置 成功职业的基础。衰老是与疾病有关的发病率和死亡率的关键危险因素 然而，影响肺部的生物学机制尚不清楚。候选人会 员工一种系统生物学方法来分析已经生成的数据集，以识别分子途径 对肺部衰老的更好理解最终可能导致新颖的发展 老年人肺部疾病的疗法。 使用RNA-SEQ进行基因表达分析已被用来通过描绘组织来生成组织的“图” 并在分子水平上纯化的一致细胞群。来自 将疾病与健康个体的疾病进行了比较，以试图开发“特征” 给定疾病。这些签名对于疾病诊断和确定目标很有用 治疗。该提案重点是肺中两个大量细胞种群的贡献 巨噬细胞和牙槽II型细胞（AT2），肺中衰老的转录特征。这 候选人有初步数据，证明了肺泡巨噬细胞中衰老的特征的证据 与3个月相比，在18个月中从小鼠纯化的AT2细胞。这种签名在影响期间仍然存在 病毒感染挑战。该建议的目的是采用系统生物学方法来分析 候选人实验室中的研究人员已经获得的转录组数据包括整个肺 在整个生命周期中从小鼠那里收集的组织，肺泡巨噬细胞和AT2细胞（2周和6,12,18，并且 24个月大）。在特定目标1中，候选人将在鼠中生成衰老的转录图 肺泡巨噬细胞和AT2细胞的全肺和纯化的细胞群。在特定的目标2中 候选人将确定肺泡巨噬细胞中衰老的转录特征是否是细胞 自主或由肺泡局部微环境的变化驱动。在这个奖项的过程中， 候选人将学习新的系统生物学方法来分析大型时间序列基因组数据集，并将 对肺部先天免疫系统的年龄相关变化有全面的了解。 作为该项目的一部分开发的技能将作为分析类似基因组数据的指南 从衰老的患有肺部疾病的衰老的人那里收获。