A Systems Biology Approach to Mapping Aging in the lung

项目摘要 NRSA个人奖学金的这一提议是出于两个总体目标：1）提供丰富的 学习和成长的环境，以支持候选人的发展成为一个有效的医生- 科学家，和2）通过应用系统生物学方法来生成肺部衰老的分子图， 在实验室小鼠的寿命期间获得的转录组学数据的分析。候选人及其 导师们设计了一个具体的培训计划，其中包括严格的研究组成部分，并奠定了 为成功的职业生涯奠定基础。老龄化是与疾病有关的发病率和死亡率的一个关键风险因素， 然而，影响肺的生物学机制尚不清楚。候选人将 采用系统生物学方法来分析已经生成的数据集，以确定 肺老化。更好地了解肺的衰老可能最终导致新的 老年人肺部疾病的治疗。 使用RNA-Seq的基因表达谱已被用于通过描绘组织来生成组织的“图谱”。 和分子水平上的纯化的组成细胞群。来自患有以下疾病的个体的转录谱 已经将疾病与来自健康个体的那些进行了比较，以试图开发出用于 鉴于疾病。这些特征可以用于疾病诊断以及用于鉴定靶点， 疗法这项建议集中在两个丰富的细胞群的贡献，在肺，肺泡 巨噬细胞和肺泡II型细胞（AT 2），在肺老化的转录签名。的 候选人有初步数据证明肺泡巨噬细胞中的衰老特征， 与3个月相比，18个月时从小鼠中纯化的AT 2细胞。这种特征在流感期间持续存在 病毒感染的挑战。本提案的目的是采用系统生物学方法来分析 研究者已在候选人实验室获得的转录组学数据，包括整个肺 组织、肺泡巨噬细胞和AT 2细胞，这些细胞是在小鼠的生命周期内（2周，6、12、18和 24个月）。在特定目标1中，候选物将在小鼠中产生衰老的转录图谱。 全肺和纯化的肺泡巨噬细胞和AT 2细胞的细胞群。具体目标2 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 自主的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 全面了解肺部先天免疫系统中与年龄相关的变化。 作为该项目一部分开发的技能将作为类似基因组数据分析的指南 是从患有肺病的老年人身上提取的

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.