Normal Aging Lung Cell Atlas (NALCA)

项目总结和U 01的补充 “正常老化肺细胞图谱”（NALCA）的总体目标，我们对RFA-HL-19-012的回应 （破译人类肺衰老的分子景观U 01），是为了产生一个纲要， mRNA、microRNA和表观遗传标记的动态细胞特异性变化发生在肺老化过程中， 关注单个细胞和肺泡微环境。我们计划利用这个纲要来产生一个动态的 正常人肺老化的时间调节模型。为了实现这一目标，我们组织了一个 肺基因组学、表观基因组学、生物工程、衰老、肺泡发育、 系统和计算生物学。这一建议的前提是资源的可用性，包括 不同年龄的正常人肺，老年野生型和老年相关的转基因小鼠，独特的 在高通量技术方面的专业知识，包括单细胞RNAseq，激光捕获显微切割， 甲基化谱分析、蛋白质组学和组织工程，以及在分析 分析时间调控网络的方法。这一目标也在很大程度上得益于与 其他不重叠的NIH-NHLBI和NIH-NIA项目由共同研究者领导。我们将 通过以下具体目的来实现本申请的目的：目的1： 微环境特异性变化的编码和非编码RNA在人类肺老化。目标2：查明 使用小鼠肺老化的详细时间分析来确定肺老化的关键时间点。目标3：制定一项 全面的转录动态调节多细胞模型的肺老化。完成这些 具体的目标将导致正常肺衰老细胞图谱的产生-科学研究的资源 社区，这将使双方更好地了解正常肺居民细胞老化，以及老化的作用， 其他慢性肺部疾病的相关机制。

PROJECT SUMMARY AND SUPPLEMENT TO U01 The overall objective of the ‘Normal Aging Lung Cell Atlas’ (NALCA), our response to RFA-HL-19-012 (Deciphering the Molecular Landscape of Lung Aging in Humans U01), is to generate a compendium of the dynamic cell specific changes in mRNA, microRNA, and epigenetic marks that happen during lung aging with a focus on single cells and the alveolar microenvironment. We plan to use this compendium to generate a dynamic temporal regulatory model of normal human lung aging. To address this objective, we have assembled a multidisciplinary group of experts in lung genomics, epigenomics, bioengineering, aging, alveolar development, systems and computational biology. The premise of this proposal lies in the availability of resources, including normal human lungs at different ages, aged wild-type and aging relevant genetically modified mice, unique expertise in high throughput technologies including single cell RNAseq, laser capture microdissection, methylation profiling, proteomics and tissue engineering, and proven track record in developmental of analytical approaches that dissect temporal regulatory networks. This objective also largely benefits from synergisms with other non-overlapping NIH-NHLBI and NIH-NIA projects headed by the coinvestigators on this proposal. We will address the objectives of this application by the following specific aims: Aim 1: To identify cell and microenvironment specific changes in coding and non-coding RNAs across human lung aging. Aim 2: To identify key time points in lung aging using detailed temporal analysis of mouse lung aging. Aim 3: To develop a comprehensive transcriptional dynamic regulatory multicellular model of lung aging. The completion of these specific aims will lead to the generation of the Normal Lung Aging Cell Atlas – a resource for the scientific community that will allow both better understanding of normal lung resident cell aging, as well as the role of aging related mechanisms in other chronic lung diseases.