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Control of progenitor cell maintenance and differentiation in the developing lung

控制发育中的肺中祖细胞的维持和分化

基本信息

批准号：
10181016
负责人：
Jason Spence
金额：
$ 48.24万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10181016
关键词：
Address Adult Alveolar Animal Model Basal Cell Biochemical Biological Models CRISPR/Cas technology Cell Differentiation process Cell Lineage Cell Maintenance Cells Complex Congenital Abnormality Coupled Cues Cultured Cells Data Decision Making Developmental Biology Distal Engraftment Environment Epithelial Extracellular Matrix Fetal Lung Fibroblast Growth Factor Fibroblasts Gene Expression Genes Genetic Genetic Models Goals Growth Growth Factor Human In Vitro Inherited Injury Knowledge Lead Lung Lung diseases MADH4 gene Maintenance Methods Molecular Morphogenesis Mus Mutation Organoids Pathway Analysis Pathway interactions Pattern Pharmacology Physical environment Population Process Regenerative Medicine Regulation Regulator Genes Research Role Sampling Signal Transduction Source Structure Testing Transcriptional Regulation Transforming Growth Factor beta Undifferentiated WNT Signaling Pathway Work campomelic dysplasia cell fate specification cell type design developmental genetics embryonic stem cell epithelial stem cell experimental study fetal genetic approach human fetus tissue human model human tissue improved in vivo induced pluripotent stem cell injured insight loss of function lung development lung regeneration lung repair mouse model mutant novel novel therapeutic intervention progenitor pulmonary function stem cell growth stem cells tool transcriptome sequencing

项目摘要

Abstract Understanding the function of lung progenitor cells is a critical to improve our fundamental understanding of lung development, but is also critical to design strategies aimed at improving lung regeneration or repair following injury. Recent evidence has demonstrated that significant functional and gene expression species- specific differences exist when comparing the developing human and mouse lung, suggesting that our fundamental understanding of human lung development is incomplete. This proposal will build on novel methods that allow us to isolate and propagate epithelial progenitor cells from developing human lungs in vitro, and novel methods to induce human lung epithelial progenitor cells from iPSCs in vitro. iPSC-derived lung progenitors are capable of long-term engraftment into the injured mouse airway where they differentiated multiple cell types within the adult murine lung. Through these studies, we have collectively defined an in vitro niche comprised of a minimal set of biochemical cues along with a physical environment (extracellular matrix) that supports lung epithelial progenitor cell growth in vitro. However, how niche factors functions to support lung epithelial progenitor maintenance and/or differentiation is unclear. This proposal will pursue aims that are designed to understand how specific niche factors mechanistically support epithelial progenitors in the developing human lung, and to interrogate the mechanisms by which human lung epithelial progenitor cells undergo cell fate specification.

摘要了解肺祖细胞的功能是提高我们对肺功能的基本理解的关键。肺发育，但也是至关重要的设计策略，旨在改善肺再生或修复受伤后。最近的证据表明，重要的功能和基因表达物种- 当比较发育中的人类和小鼠肺时，存在特定的差异，这表明我们的对人类肺发育的基本认识是不完整的。该提案将建立在新的这些方法使我们能够在体外从发育中的人肺中分离和繁殖上皮祖细胞，以及从iPSC体外诱导人肺上皮祖细胞的新方法。iPSC衍生肺祖细胞能够长期移植到它们分化的损伤小鼠气道中成年鼠肺内的多种细胞类型。通过这些研究，我们共同定义了体外生态位由一组最小的生化线索沿着物理环境（细胞外基质）组成支持肺上皮祖细胞体外生长的药物。然而，利基因素如何发挥作用，肺上皮祖细胞的维持和/或分化尚不清楚。这项建议将追求以下目标：旨在了解特定的生态位因子如何机械地支持上皮祖细胞，发展人肺，并询问机制，人肺上皮祖细胞经历细胞命运规范化。