Research Center for Spatiotemporal Lung Imaging and Omics

项目摘要 肺泡形成是人类正常肺发育的后期特征，也是肺发育的最后一步。 成熟。肺泡形成是一个动态的、协调的过程，需要准确的空间和时间 整合信号以形成错综复杂的肺泡结构。虽然取得了重要进展， 在我们对潜在的分子机制的理解中仍然存在着重大的知识空白 肺泡发育。出于这个原因，NHLBI建立了研究中心(RCS)来创建一份分子图谱 肺发育(LUNgMAP)主要集中在出生至儿童早期(~8岁)。在第一阶段 LongMAP，我们的RC开发了资源，使我们能够更详细地了解正常肺 发展到儿童早期。在第二阶段，我们将应用我们成功的方法和我们的 将肺发育分析扩展到成人早期和人类疾病的最新技术； 关注支气管肺发育不良(BPD)，早产儿最常见的发病率是 以肺成熟延迟或不足为特征。 在肺内，空间、解剖和功能之间的关系是基本的。因此，我们的 方法包括新的无偏3D定量成像方法，实现了高空间 分辨率以及细胞特异性组学：蛋白质组学(包括基于活性的蛋白质组学和 磷蛋白质组学)、类脂组学和代谢组学。整合这些互补数据收集 方法有助于建立具有令人难以置信的分子广度的特定细胞空间图谱 在正常和疾病状态下整个发育中的肺的轮廓。 具体地说，我们将通过以下途径实现建立完整的肺发育分子图谱的目标 目标如下：(1)正常和疾病状态下的人肺分子图谱的空间成像，(2) 正常和疾病状态下人类肺的分子图谱的细胞特异性组学，以及(3)管理 数据，以促进协作和数据集成。 总体而言，这些目标将创造出史无前例的多尺度可浏览的量化三维谷歌 蛋白质、脂肪和代谢物在整个肺发育过程中的“图谱”，提供了许多新的见解 有助于了解人类正常的肺部生物学和疾病发病机制。 新的成像方法和一套集成的泛组学能力(即蛋白质组学， 磷蛋白质组学、基于活性的蛋白质组学、脂类组学和代谢组学)开发并在 PNNL的单一实验室代表了研究中心的独特优势。

PROJECT ABSTRACT Alveologenesis characterizes the later stages of normal human lung development and is the final step of lung maturation. Alveologenesis is a dynamic, coordinated process that requires the accurate spatial and temporal integration of signals to develop the intricate alveolar structure. While important progress has been made, significant knowledge gaps remain in our understanding of the molecular mechanisms underlying alveologenesis. For this reason, NHLBI established Research Centers (RCs) to create a molecular atlas of the developing lung (LungMAP) focused from birth up to early childhood (~8 years). In the first phase of LungMAP, our RC developed resources that enabled a much more detailed understanding of normal lung development up to early childhood. In LungMAP Phase 2, we will apply our successful approaches and our newest technologies to extend analysis of lung development into early adulthood as well as human disease; focusing on bronchopulmonary dysplasia (BPD), the most common morbidity of preterm infants which is characterized by delayed or deficient lung maturation. Within the lung, the relationship between space, anatomy, and function is fundamental. Therefore, our approach includes new unbiased 3D quantitative imaging approaches implemented with high spatial resolution, as well as cell-specific omics: proteomics (including activity-based proteomics and phosphoproteomics), lipidomics, and metabolomics. The integration of these complementary data collection methods facilitates the establishment of a cell-specific spatial atlas with an incredible breadth of molecular profiles across the developing lung in normal and disease states. Specifically, we will accomplish our goal of an integrated molecular atlas of lung development through the following aims: (1) Spatial imaging for a molecular atlas of the human lung in normal and diseased states, (2) Cell-specific omics for a molecular atlas of the human lung in normal and diseased states, and (3) Managing data to facilitate collaboration and data integration. Overall, these aims will create unprecedented multi-scale browsable quantitative three-dimensional “Google Maps” of proteins, lipids, and metabolites across the developing lung, providing for many novel insights toward understanding both normal human lung biology and disease pathogenesis. The novel imaging approaches and the suite of integrated pan-omics capabilities (i.e. proteomics, phosphoproteomics, activity-based proteomics, lipidomics and metabolomics) developed and available in a single laboratory at PNNL represents a unique strength of the Research Center.