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.

Public Health Relevance

The Strategic Goal of this UO1 proposal is to construct a rich multiscale atlas of human alveolar development in collaboration with other research centers, the tissue procurement center and the data management center so that LungMAP can be openly interrogated and shared with the research community.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHL1)
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Lin, Sara
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Children's Hospital of Los Angeles
Los Angeles
United States
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Luo, Yongfeng; Li, Nan; Chen, Hui et al. (2018) Spatial and temporal changes in extracellular elastin and laminin distribution during lung alveolar development. Sci Rep 8:8334
Warburton, David (2017) Overview of Lung Development in the Newborn Human. Neonatology 111:398-401
Davies, Joanna M S; Cillard, Josiane; Friguet, Bertrand et al. (2017) The Oxygen Paradox, the French Paradox, and age-related diseases. Geroscience 39:499-550
Buckley, Susan; Shi, Wei; Xu, Wei et al. (2015) Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J 46:1417-29