Cell Biology of Airway Epithelial Basal Cell Progenitors

气道上皮基底细胞祖细胞的细胞生物学

• 批准号: 7907447
• 负责人: Jason Randall Rock
• 金额: $ 5.05万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-14 至 2011-07-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907447
• 关键词: Affect; American; Asthma; Back; Basal Cell; Biological Assay; Biology; Bronchi; Bronchioles; Cell Therapy; Cells; Cellular biology; Chronic; Chronic lung disease; Collaborations; Confocal Microscopy; Cystic Fibrosis; Data; Development; Disease; Epithelial; Epithelial Cells; Gases; Genetic; Health; Homeostasis; Human; Immune; In Vitro; Interleukin-13; Life; Light; Lung; Lung diseases; Maintenance; Malignant Neoplasms; Molecular; Molecular and Cellular Biology; Mus; Neuroendocrine Cell; Population; Pseudostratified Epithelium; Signal Transduction; Stem cells; Structure; Structure of respiratory epithelium; Testing; Tissues; Trachea; Training; Transgenic Mice; cell behavior; cell type; cytokine; in vivo; mouse model; multidisciplinary; novel; oxygen transport; progenitor; public health relevance; research study; self-renewal; stem cell biology

DESCRIPTION (provided by applicant): Airways (i.e. the trachea, bronchi, and bronchioles) that transport oxygen to the lungs for gas exchange are essential to human life. The largest airways of mice, and all human conducting airways, are lined with a pseudostratified epithelium made up of roughly equal numbers of secretory (Clara), ciliated, and basal cells and sparse neuroendocrine cells. The abundance, distribution, and function of these epithelial cells are disrupted in debilitating lung diseases such as chronic asthma, cystic fibrosis, and cancer. Recent evidence from our lab has shown that basal cells self-renew and generate differentiated Clara and ciliated cells over 14 weeks in vivo and for at least three passages in vitro. Therefore, as a progenitor population, basal cells have the potential to regulate the composition of the whole respiratory epithelium. Moreover, the identification of a population capable of long-term self-renewal and differentiation is critical for the development of cell-based therapies for lung diseases. By combining long-term genetic lineage tracing with confocal microscopy and collaborations with stem cell experts, Specific Aim 1 of this proposal will test the hypothesis that a subset of basal cells, residing in a highly vascularized niche, self-renews over very long periods. In Specific Aim 2, a novel assay will be used to test the hypothesis that components of the basal cell niche modulate their cell biology, self-renewal, and differentiation. Preliminary data has shown that IL13, a cytokine known to alter epithelial structure and function in chronic asthma, affects numerous basal cell behaviors in this assay in the absence of other cell types (e.g. stroma, immune cells). We will exploit this assay and transgenic mouse lines to test the functions of Bmp signaling in the maintenance of airway epithelial homeostasis. In the longer term, this assay will be used to identify novel effectors of basal cell behaviors and these findings will be related back to life using mouse models. In addition to providing multidisciplinary training in cell biology, lung (patho) biology, and stem cell biology, these data will throw new light on the contributions of progenitor cell behaviors to health and disease. PUBLIC HEALTH RELEVANCE: More than 35 million Americans live with chronic lung diseases - many of which involve changes in the structure and function of the respiratory epithelium. Basal cells, as a progenitor population in the airways of mice and humans, affect the overall tissue composition of conducting airways. The experiments outlined herein will answer outstanding questions related to the cell and molecular biology of basal cells and pave the way for the identification of novel molecular and cell-based therapies of lung diseases.

描述（由申请人提供）：将氧气运送到肺部以进行气体交换的气道（即气管，支气管和支气管菌）对人类的生命至关重要。小鼠的最大气道和所有人类导电道衬有伪分层的上皮，由大约相等数量的分泌（Clara），纤毛和基底细胞以及稀疏的神经内分泌细胞组成。这些上皮细胞的丰度，分布和功能在使人衰弱的肺部疾病（例如慢性哮喘，囊性纤维化和癌症）中受到破坏。我们实验室的最新证据表明，基底细胞在体内和至少三个体外段落中自我更新并产生分化的克拉拉和纤毛细胞。因此，作为祖细胞种群，基底细胞有可能调节整个呼吸上皮的组成。此外，鉴定能够长期自我更新和分化的人群对于开发基于细胞的肺部疾病的疗法至关重要。通过将长期的遗传谱系跟踪与共聚焦显微镜和与干细胞专家的合作相结合，该提案的特定目的1将检验以下假设：基底细胞的子集在很长一段时间内居住在高度血管化的细分市场中。在特定的目标2中，将使用一种新的测定方法来检验以下假设：基底细胞小裂的成分调节其细胞生物学，自我更新和分化。初步数据表明，IL13是一种已知会改变慢性哮喘上皮结构和功能的细胞因子，在没有其他细胞类型的情况下会影响这种测定中的许多基础细胞行为（例如，质膜，免疫细胞）。我们将利用该测定和转基因小鼠系来测试BMP信号在维持气道上皮稳态中的功能。从长远来看，该测定法将用于识别基底细胞行为的新型效应因子，这些发现将使用小鼠模型与生活有关。除了提供细胞生物学，肺（Patho）生物学和干细胞生物学的多学科培训外，这些数据还将对祖细胞行为对健康和疾病的贡献进行新的启示。 公共卫生相关性：超过3500万美国人患有慢性肺部疾病 - 其中许多涉及呼吸上皮的结构和功能的变化。基底细胞是小鼠和人类气道中的祖细胞，会影响导电道的整体组织组成。本文概述的实验将回答与基底细胞的细胞和分子生物学有关的未来问题，并为鉴定新的分子和基于细胞的肺部疾病疗法铺平了道路。