Molecular anatomy of human alveolar development

描述(由申请人提供)：以下目标旨在实现总体战略目标，即构建丰富的多尺度人类肺泡发育图集，并随时与UO1的其他研究中心和广泛的研究社区共享由此产生的材料。目标1.使用新的微型CT(UCT)、微型磁共振成像(UMRI)和相位对比X射线(PCX)技术，绘制一张在体内和组织块中随时间变化的肺泡发育的数字地图，该技术在小鼠和人类肺组织中得到验证。目标2：利用新近改进的高通量多路复用器和新颖的“切片和骰子”Vibra-Ssim共聚焦技术，在小鼠和人肺组织中制作一张随时间推移的肺泡发育过程中基因时空表达的数字地图。目标3：制作小鼠和人类组织发育过程中肺泡基质精细结构的数字地图。目标4.开发图像处理技术，将肺泡结构、细胞自主基因表达和细胞外基质蛋白构型的数字多尺度图像融合为科学界易于导航、带注释的新数据资源。将制定标准操作规程，并设立流程驱动的里程碑，以确保这项重大科学投资的交付能力和回报。Warburton、Shih和Driscoll博士是肺泡生物学家，而Fraser、Moats和Lansford博士是成像专家，他们擅长记录、登记和汇编果蝇和小鼠器官发育的数字、多尺度组合地图，并发明了许多新颖和高度创新的技术来做到这一点。对人类健康的总体影响：人类和小鼠的肺在结构上是根本不同的(在Warburton等人，2010年进行了审查)。小鼠和人在胎长、分叶、气道分支类型、气道分支数目、近远端气道上皮细胞分化、肺泡上皮和毛细血管表面积以及肺泡上皮细胞数等方面存在重要差异。尤其重要的是，肺泡化在小鼠出生后就开始了，但在人类的子宫中就开始了。我们建议最终将我们关于小鼠肺泡发育的新概念迅速转化为在人类体内的研究。我们希望这些基础知识最终将有助于预防和治疗肺泡发育不良，如发生在人类早产儿的支气管肺发育不良中，以及潜在地为肺泡组织的再生或改善或逆转患有肺部疾病的年龄较大的儿童、青少年和成人的肺泡变性提供信息。(摘要结束)

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)