Regulation of mesenchymal cells by epithelial Wnt ligands

上皮Wnt配体对间充质细胞的调节

• 批准号: 10471778
• 负责人: Jichao Chen
• 金额: $ 60.82万
• 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: 2016-03-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471778
• 关键词: Adult; Alleles; Alveolar; Area; Biological; Bronchopulmonary Dysplasia; Cells; Data; Development; Disease; Embryo; Endothelial Cells; Epigenetic Process; Epithelial; Epithelial Cells; Failure; Future; Genes; Genetic; Genetic Transcription; Genomics; Grant; Hyperoxia; Investigation; Ligands; Lung; Mediating; Mesenchymal; Mesenchyme; Modeling; Molecular; Morphogenesis; Mutant Strains Mice; Myofibroblast; Neonatal Hyperoxic Injury; PDGFRA gene; Pathway interactions; Pericytes; Phenocopy; Phenotype; Process; Publishing; Regulation; Research; Role; Signal Pathway; Signal Transduction; Source; Surface; TCF Transcription Factor; TP53 gene; Testing; Three-Dimensional Imaging; To specify; VEGFA gene; Vascular Endothelial Growth Factors; WNT Signaling Pathway; Work; cell type; conditional mutant; epigenomics; gene environment interaction; genomic tools; insight; mouse genetics; mutant; neonatal period; novel; paralogous gene; postnatal; single-cell RNA sequencing; transcriptomics

PROJECT SUMMARY Alveologenesis requires co-development of the epithelium, mesenchyme, and vasculature, the failure of which is a cardinal feature of bronchopulmonary dysplasia (BPD). This process depends on precisely controlled intercellular signaling, such as Fgf, Pdgf, Shh, and Vegf signaling, as revealed by recent work including ours in the previous grant period. Another major signaling pathway, Wnt signaling, extensively studied in embryonic lungs and potentially involved in adult lungs, is poorly understood in the neonatal period. Moreover, published Wnt studies focus on epithelial cells, but largely ignore the robust expression of Wnt target genes within the postnatal mesenchyme. Further contributing to our limited understanding of mesenchymal Wnt signaling is lack of clarity on the cell types in the mesenchyme, which starts to be unveiled via single-cell genomics. By following the unexpected signaling role of AT1 cells in the previous grant period, we have obtained evidence that epithelial WNT ligands specifically signal toward myofibroblasts during alveologenesis. Pursuing, as proposed, the signaling cells (Aim 1), the receiving cells (Aim 2), and the disease relevance (Aim 3) is expected to not only elucidate the little-known mesenchymal Wnt signaling, but also establish an experimental paradigm applicable to future lung mesenchyme research.

项目总结