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.

项目概要 这项 NRSA 个人奖学金提案的动机是两个总体目标：1）提供丰富的 学习和成长的环境，以支持候选人发展成为一名有效的医生- 科学家，2) 通过应用系统生物学方法来生成肺部衰老的分子图 对实验室小鼠一生中获得的转录组数据进行分析。 导师设计了一个具体的培训计划，其中包括严格的研究部分，并奠定了 老龄化是与疾病相关的发病率和死亡率的一个关键风险因素。 影响肺部，然而，其生物学机制尚不清楚。 采用系统生物学方法来分析已经生成的数据集，以确定分子途径 更好地了解肺部衰老可能最终会导致新型药物的开发。 老年人肺部疾病的治疗方法。 使用 RNA-Seq 进行基因表达谱分析已被用于通过描绘组织来生成组织“图谱” 以及在分子水平上纯化的细胞组成群的转录谱。 人们将疾病与健康个体的疾病进行比较，试图开发出疾病的“特征”。 这些特征可用于疾病诊断以及识别目标。 该提案重点关注肺、肺泡中两种丰富细胞群的贡献。 巨噬细胞和肺泡 II 型细胞 (AT2) 参与肺部衰老的转录特征。 候选人有初步数据证明肺泡巨噬细胞老化特征的证据， 与 3 个月相比，在 18 个月时从小鼠中纯化的 AT2 细胞在流感期间仍然存在。 该提案的目的是采用系统生物学方法进行分析。 研究人员已在候选人实验室获得的转录组数据，包括整个肺 在整个生命周期（2周、6、12、18和 24 个月大）在具体目标 1 中，候选人将生成小鼠衰老的转录图谱。 在特定目标 2 中，全肺以及肺泡巨噬细胞和 AT2 细胞的纯化细胞群。 候选人将确定肺泡巨噬细胞衰老的转录特征是否是细胞 自主的或由肺泡局部微环境的变化驱动。 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 全面了解肺部先天免疫系统与年龄相关的变化。 作为该项目一部分开发的技能将作为分析类似基因组数据的指南 从患有肺病的老年人身上采集。