Role of AT1 cells in perinatal lung maturation

AT1细胞在围产期肺成熟中的作用

• 批准号: 9889162
• 负责人: Jichao Chen
• 金额: $ 39.58万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-16 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889162
• 关键词: Abbreviations; Address; Alveolar; Angiogenic Factor; Attention; Blood Vessels; Blood capillaries; Bronchopulmonary Dysplasia; Cell Count; Cell Differentiation process; Cell Size; Cells; Complement; Data; Development; Ectopic Expression; Endothelial Cells; Endothelium; Epithelial; Epithelium; Fibroblasts; Functional disorder; Gases; Gene Expression; Genes; Genetic; Genetic Models; Goals; Hyperoxia; Individual; Interruption; Knowledge; Life; Link; Lung; Lung diseases; Modeling; Molecular; Morphogenesis; Morphology; Mus; Nuclear Export; Pathogenesis; Pathologic; Perinatal; Phenotype; Premature Birth; Process; Regulation; Risk Factors; Role; Signal Transduction; Source; Structure; Surface; Testing; Thinness; VEGFA gene; alveolar epithelium; angiogenesis; cell growth; cellular imaging; imaging genetics; imaging modality; in vitro Assay; insight; lung maturation; mutant; novel; public health relevance; quantitative imaging; stem cells; surfactant production; tool; transcription factor

 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.

 描述（由申请人提供）：围产期肺成熟允许过渡到独立的子宫外生活，需要上皮气体交换表面和并列毛细血管的协调扩张。早产中断这一过程是严重肺部疾病的主要风险因素，例如支气管肺发育不良（BPD），通常表现为肺泡简化和畸形毛细血管。虽然覆盖>95%的肺泡表面并覆盖大部分肺泡脉管系统，但肺泡1型（AT 1）细胞传统上被认为是被动结构组分，并且由于其干细胞潜力和在表面活性剂产生中的作用，注意力集中在肺泡2型（AT 2）细胞上。 这与研究超薄（<0.1 μ m）AT1细胞延伸的技术挑战相结合，导致我们对AT1细胞在正常和病理性肺泡发生中的作用的知识有限。深入了解AT1细胞在发育过程中是必要的，以赶上最近的进展，研究AT2细胞和成纤维细胞，以获得围产期肺成熟的全貌。我们的初步数据支持一个新的假设，即AT1细胞在协调肺泡形态发生和血管生成在围产期肺成熟的信号作用。这项建议有以下三个具体目标。(1)确定AT1细胞发育是否促进肺泡血管生成。(2)目的探讨AT 1细胞源性血管生成因子是否促进肺泡血管生成。(3)确定AT1细胞功能障碍是否有助于高氧诱导的肺泡简化。总之，该提案采用新的定量成像和遗传工具来研究AT 1细胞在围产期肺成熟中的知之甚少和意想不到的作用，并代表了我们阐明肺不成熟机制和治疗的长期目标的一步。