Role of AT1 cells in perinatal lung maturation

 描述(申请人提供)：围产期肺成熟可以过渡到独立的宫外生活，需要上皮气体交换面和并列的毛细血管协调扩张。早产对这一过程的干扰是严重肺部疾病的主要危险因素，如支气管肺发育不良(BPD)，通常表现为肺泡简化和毛细血管畸形。虽然肺泡I型(AT1)细胞覆盖了肺泡表面的95%，覆盖了大部分的肺泡血管，但传统上被认为是一种被动的结构成分，由于其干细胞的潜力和在表面活性物质产生中的作用，人们的注意力一直集中在肺泡2型(AT2)细胞上。 这一点，再加上研究超薄(&lt；0.1um)AT1细胞延伸的技术挑战，导致我们对AT1细胞在正常和病理性肺泡形成中的作用了解有限。为了跟上AT2细胞和成纤维细胞研究的最新进展，以获得围产期肺成熟的完整图像，有必要对AT1细胞发育过程进行深入了解。我们的初步数据支持一种新的假设，即AT1细胞在围产期肺成熟过程中具有协调肺泡形态发生和血管生成的信号作用。这项建议有以下三个具体目标。(1)探讨AT1细胞发育是否促进肺泡血管生成。(2)探讨AT1细胞源性血管生成因子是否促进肺泡血管生成。(3)探讨AT1细胞功能障碍是否与高氧诱导的肺泡简化有关。综上所述，这项建议使用了新的定量成像和基因工具来研究AT1细胞在围产期肺成熟中鲜为人知和意想不到的作用，并代表着我们朝着阐明肺不成熟的机制和治疗的长期目标迈出了一步。

 DESCRIPTION (provided by applicant): Perinatal lung maturation allows transition to independent extrauterine life and requires concerted expansion of the epithelial gas exchange surface and the juxtaposed capillaries. Interruption of this process by premature birth is a major risk factor for serious lung diseases, such as bronchopulmonary dysplasia (BPD) that frequently manifests as alveolar simplification and dysmorphic capillaries. Although covering >95% of the alveolar surface and overlaying most of the alveolar vasculature, alveolar type 1 (AT1) cells are traditionally considered a passive structural component and attention has been focused on alveolar type 2 (AT2) cells because of their stem cell potential and role in surfactant production. This, combined with technical challenges in studying the ultra-thin (<0.1 um) AT1 cell extensions, results in our limited knowledge of the role of AT1 cells in normal and pathological alveologenesis. An in-depth understanding of AT1 cells during development is necessary to catch up with recent progress in studying AT2 cells and fibroblasts to obtain a complete picture of perinatal lung maturation. Our preliminary data support a novel hypothesis that AT1 cells have a signaling role in coordinating alveolar morphogenesis and angiogenesis during perinatal lung maturation. This proposal has the following three specific aims. (1) To determine whether AT1 cell development promotes alveolar angiogenesis. (2) To determine whether AT1 cell derived angiogenic factors promote alveolar angiogenesis. (3) To determine whether AT1 cell dysfunction contributes to hyperoxia-induced alveolar simplification. In summary, this proposal employs novel quantitative imaging and genetic tools to study the poorly understood and unexpected role of AT1 cells in perinatal lung maturation, and represents a step toward our long term goal of elucidating mechanisms and therapies of lung immaturity.