Molecular anatomy of human alveolar development

人类肺泡发育的分子解剖学

• 批准号: 8870424
• 负责人: DAVID WARBURTON
• 金额: $ 80.58万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870424
• 关键词: Adolescent; Adult; Alveolar; Alveolus; Anatomy; Area; Atlases; Biology; Blood Vessels; Blood capillaries; Boxing; Breathing; Bronchopulmonary Dysplasia; Cell Count; Cells; Chest; Child; Collaborations; Communities; Custom; Data; Development; Diagnostic radiologic examination; Distal; Dose; Drosophila genus; Ensure; Epithelial; Epithelial Cells; Event; Extracellular Matrix Proteins; Film; Fluorescent in Situ Hybridization; Four-dimensional; Future; Gene Expression; Goals; Health; Histology; Human; Image; Immunohistochemistry; In Situ Hybridization; Inferior; Investments; Knowledge; Length; Lobe; Lung; Lung diseases; Lymphatic; Magnetic Resonance Imaging; Maps; Mesenchymal; Microanatomy; Molecular; Molecular Genetics; Monkeys; Mus; Natural regeneration; Paraffin Embedding; Pattern; Phase; Plastic Embedding; Pregnancy; Prevention; Procedures; Process; Publishing; Radiation; Research; Resolution; Resources; Roentgen Rays; Scanning; Scientist; Selection Bias; Slice; Staging; Structure; Structure of parenchyma of lung; Surface; Techniques; Technology; Third Pregnancy Trimester; Time; Tissue Procurements; Tissues; Translating; Work; abstracting; capillary; combinatorial; data management; design; digital; digital imaging; human tissue; image processing; in utero; in vivo; innovation; lung development; lung maturation; microCT; neonate; novel; organ growth; postnatal; premature; relating to nervous system; spatiotemporal; surfactant; time use

DESCRIPTION (provided by applicant): The following Goals are designed to achieve the overarching Strategic Goal to construct a rich multiscale atlas of human alveolar development and to readily share the resulting materials with other research centers in the UO1 and with the broad research community. Goal 1. Make a digital map of alveolar development over time in vivo and in tissue pieces using novel micro- CT (uCT), micro MRI (uMRI) and Phase contrast X-ray (PCX) technology validated in mice and then in human lung tissue. Goal 2. Make a digital map of spatiotemporal gene expression during alveolar development over time using newly modified high throughput multiplex ISH with novel "slice and dice", Vibra-SSIM confocal technology, in mouse and human lung tissue. Goal 3. Make a digital map of the fine structure of alveolar matrix during development in mouse and human tissue. Goal 4. Develop image-processing technology to meld digital multiscale images of alveolar structure with cell autonomous gene expression with extracellular matrix protein configuration into a readily navigable, annotated novel data resource for the scientific community. SOPs will be developed and process driven milestones will be set up to ensure deliverability and return on this significant scientific investment. Drs. Warburton, Shi and Driscoll are expert alveolar biologists while Drs. Fraser, Moats and Lansford are expert imaging scientists who are adept at recording, registering and assembling digital, multiscale combinatorial maps of organ development in Drosophila and Mouse and have invented many novel and highly innovative techniques to do so. Overall impact on human health: Human and mouse lung are fundamentally structurally different (reviewed in Warburton et al, 2010). Length of gestation, lobation, airway branch pattern, number of airway branches, proximo-distal airway epithelial differentiation and alveolar epithelial and capillary surface area as well as alveolar epithelial cell number differ in importan respects between mouse and human. Not least, alveolarization begins postnatally in mice, yet begins in utero in humans. We propose eventually to translate our novel concepts on alveolar development derived in mice rapidly to studies in vivo in humans. We hope that this fundamental knowledge will eventually be useful for the prevention and treatment of alveolar hypoplasia, such as occurs in bronchopulmonary dysplasia of the human premature neonate, as well as potentially to informing regeneration of alveolar tissue or amelioration or reversal of alveolar degeneration in older children, adolescents and adults with lung diseases. (End of Abstract)

描述（由申请人提供）：以下目标旨在实现总体战略目标，即构建丰富的人类肺泡发育的多尺度图谱，并轻松与 UO1 的其他研究中心和广泛的研究界共享所得材料。目标 1. 使用在小鼠和人体肺组织中验证的新型微型 CT (uCT)、微型 MRI (uMRI) 和相差 X 射线 (PCX) 技术，绘制体内和组织片中肺泡随时间变化的数字图。目标 2. 使用新改良的高通量多重 ISH 和新颖的“切片和切块”Vibra-SSIM 共聚焦技术，在小鼠和人类肺组织中绘制肺泡发育过程中随时间变化的时空基因表达的数字图谱。目标 3. 绘制小鼠和人体组织发育过程中肺泡基质精细结构的数字图。目标 4. 开发图像处理技术，将肺泡结构的数字多尺度图像与细胞自主基因表达和细胞外基质蛋白配置融合成科学界易于导航、带注释的新型数据资源。将制定标准操作程序并设立流程驱动的里程碑，以确保这项重大科学投资的可交付性和回报。博士。 Warburton、Shi 和 Driscoll 是肺泡生物学专家，而 Drs.弗雷泽、莫茨和兰斯福德是成像专家，擅长记录、登记和组装果蝇和小鼠器官发育的数字化、多尺度组合图，并为此发明了许多新颖且高度创新的技术。对人类健康的总体影响：人类和小鼠的肺在结构上根本不同（Warburton 等人，2010 年综述）。小鼠和人类之间的妊娠时长、分叶、气道分支模式、气道分支数量、近远端气道上皮分化、肺泡上皮和毛细血管表面积以及肺泡上皮细胞数量在重要方面存在差异。尤其重要的是，小鼠的肺泡化是在出生后开始的，而人类则是在子宫内开始的。我们最终建议将小鼠肺泡发育的新概念快速转化为人类体内研究。我们希望这一基础知识最终将有助于预防和治疗肺泡发育不全，例如发生在人类早产儿的支气管肺发育不良中，并有可能为患有肺部疾病的年龄较大的儿童、青少年和成人的肺泡组织再生或改善或逆转肺泡变性提供信息。 （摘要完）