Decoding the Cellular Niches Critical for Lung Maturation and Pathogenesis

项目总结 人类的肺是巨大的器官，具有精致的地区差异，其形式为 单细胞分辨率最好定义的细胞利基。新出现的证据导致越来越多的 认识到这些精细专业化认证的集体作用是 肺功能。以科学假设为指导，这些壁龛通常是 发病机制，我们建议在正常和疾病组织中定位这些生态位，并 在单元格分辨率下直接比较它们。这一目标直接响应了 第二阶段的使命是“扩展到更具体和更稀有的细胞类型”。 为了实现这一目标，我们召集了一支由成熟的和 正在崛起的基础和临床研究人员在发展方面优势互补 生物学(Sun)，细胞生物学和免疫学(普林斯，Sajti)，技术开发和 信息学(Ren，Preissl，Wang，Xu)。在一起，我们有学习的记录 控制正常的肺成熟，以及一些潜在的机制 肺图-突出疾病，包括支气管肺发育不良，先天性 横隔疝、儿童间质性肺疾病和儿童肺 高血压(PPH)。我们将使用单核等尖端技术 ATACseq、单细胞和单核RNAseq、多重抗体和原位RNA 杂交和三维成像。利用这些，我们将系统地定义 人类肺中令人兴奋的细胞类型万花筒，重点是细胞 在致病机制中起中心作用的小生境。

PROJECT SUMMARY The human lung is vast organ with exquisite regional differences in the form of cellular niches best defined at single-cell resolution. Emerging evidence led to growing appreciation that the collective roles of these fine specializations are fundamental for lung function. Guided by the scientific premise that these niches are often sites of pathogenesis, we propose to map these niches in normal and disease tissues and directly compare them at the single-cell resolution. This goal is directly responsive to the mission of LungMap Phase 2 to “extend to more specific and rare cell types.” To achieve this goal, we have gathered an interdisciplinary team of established and rising, basic and clinical investigators with complementary strengths in developmental biology (Sun), cell biology and immunology (Prince, Sajti), technology development and informatics (Ren, Preissl, Wang and Xu). Together, we have a track record of studying the control of normal lung maturation, as well as mechanisms underlying a number of LungMap-highlighted diseases, including bronchopulmonary dysplasia, congenital diaphragmatic hernia, childhood interstitial lung disease, and pediatric pulmonary hypertension (PPH). We will use cutting-edge technologies such as single-nucleus ATACseq, single-cell and single-nucleus RNAseq, multiplex antibody and RNA in situ hybridization, and three-dimensional imaging. Using these, we will systematically define the exciting kaleidoscope of cell types in the human lung, with an emphasis on cellular niches that are central to pathogenesis.