Decoding the Cellular Niches Critical for Lung Maturation and Pathogenesis

项目摘要 人的肺是一个巨大的器官，在形态上存在着微妙的区域差异。 细胞小生境最好在单细胞分辨率下定义。新出现的证据导致 认识到这些精细专业化的集体作用是基础， 肺功能在科学前提的指导下，这些壁龛往往是 发病机制，我们建议在正常和疾病组织中绘制这些小生境， 直接在单细胞分辨率下比较它们。这一目标直接响应了 LungMap第二阶段的使命是“扩展到更特异和罕见的细胞类型”。 为了实现这一目标，我们聚集了一个跨学科的团队， 新兴的基础和临床研究人员，在发展方面具有互补优势 生物学（Sun），细胞生物学和免疫学（Prince，Sajti），技术开发和 信息学（Ren，Preissl，Wang和Xu）。我们一起研究了 正常肺成熟的控制，以及一些潜在的机制， 肺图突出显示的疾病，包括支气管肺发育不良、先天性 疝、儿童间质性肺病和小儿肺 高血压（PPH）。我们将使用尖端技术，如单核 ATACseq、单细胞和单核RNAseq、多重抗体和RNA原位 杂交和三维成像。利用这些，我们将系统地定义 人类肺部细胞类型的令人兴奋的万花筒，重点是细胞 对发病机制至关重要的小生境。

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.