Cell-cell interactions governing lung epithelial progenitor cells

细胞间相互作用控制肺上皮祖细胞

• 批准号: 10331831
• 负责人: Carla F. Kim
• 金额: $ 88.5万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331831
• 关键词: 3-Dimensional; Adult; Alveolar; Biological Assay; Biological Process; Biology; Cataloging; Cell Communication; Cells; Coculture Techniques; Communities; Development; Endothelial Cells; Environment; Epithelial; Focus Groups; Homeostasis; Human; Lung; Lung diseases; Malignant neoplasm of lung; Mesenchymal; Methods; Modeling; Molecular; Organoids; Regenerative Medicine; Research; Role; Signal Transduction; Stem cell transplant; Structure; Structure of parenchyma of lung; Supporting Cell; System; Techniques; Therapeutic Intervention; Therapeutic Uses; Transplantation; cell type; epithelial stem cell; injury and repair; lung injury; mouse model; novel strategies; paracrine; progenitor; programs; repaired; response to injury; single-cell RNA sequencing; stem cell biology; stem cells; tool

Summary My lab’s contributions have helped bring lung biology to the forefront of stem cell biology. Our major focus has been to develop tools to characterize progenitor cells in the adult lung and in lung cancer; I now aim to develop this expertise for applications in lung diseases. We created three-dimensional co-culture organoid systems that have begun to define cell-cell crosstalk between epithelial progenitors and other supporting cell types in the lung. We can now model the formation of airway- and alveolar-like structures from lung progenitor cells, and we have a platform to understand differentiation control at the molecular level. This research program seeks to build on our advances and to further develop lung organoids to interrogate the molecular underpinnings of cell-cell interactions between epithelial progenitor cells and their environment in the adult lung homeostasis and in diseased lung. We will determine the signals through which epithelial progenitors are regulated by mesenchymal cells and endothelial cells during lung injury response and repair. Cells from mouse models of lung disease will be used for single cell RNA-sequencing and in organoid systems to identify cell autonomous and paracrine mechanisms that can be used for therapeutic intervention. We will refine our techniques for use with human lung cells. We will create a lung progenitor cell transplantation assay, a critical need in the lung community for the study of progenitors and for regenerative medicine. While other groups are focused on cataloging lung cell types, our strategies will provide essential tools to interrogate the biological functions of diverse lung cells. Collectively, these new approaches will allow us to continue to build and utilize transformative methods to probe numerous aspects of the biology of normal lung and lung disease.

总结 我的实验室的贡献有助于将肺生物学带到干细胞生物学的前沿。我们的重点是 我一直在开发工具来表征成人肺和肺癌中的祖细胞;我现在的目标是开发 这种专业知识在肺部疾病中的应用。我们创造了三维共培养类器官系统 已经开始定义上皮祖细胞和其他支持细胞类型之间的细胞间串扰， 肺我们现在可以模拟肺祖细胞形成气道和肺泡样结构， 我们有一个平台来了解分子水平上的分化控制。这个研究项目 寻求建立在我们的进步，并进一步开发肺类器官，以询问分子 成人肺上皮祖细胞与其环境间细胞-细胞相互作用的基础 内环境稳定和病变肺。我们将确定上皮祖细胞通过哪些信号 在肺损伤反应和修复过程中受到间充质细胞和内皮细胞的调节。细胞 肺部疾病的小鼠模型将用于单细胞RNA测序和类器官系统，以确定 细胞自主和旁分泌机制，可用于治疗干预。我们将完善我们的 用于人类肺细胞的技术。我们将建立一种肺祖细胞移植试验， 需要在肺社区的祖细胞和再生医学的研究。而其他群体则 我们的策略专注于对肺细胞类型进行分类，将提供必要的工具， 不同肺细胞的功能。总的来说，这些新方法将使我们能够继续建立和利用 变革性的方法来探索正常肺和肺部疾病的生物学的许多方面。