Alveolar Tissuegenesis

肺泡组织发生

• 批准号: 6789290
• 负责人: William J Martin
• 金额: $ 24.19万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789290
• 关键词: DNA damage; bleomycin; histogenesis; laboratory mouse; lung injury; nonhuman therapy evaluation; regeneration; respiratory epithelium; stem cell transplantation; transfection

DESCRIPTION (provided by applicant): Acute lung injury is characterized by diffuse alveolar damage with injury and death of type I and type II alveolar epithelial cells. Injury to the type II cell is particularly critical as it is the progenitor of the type I cell and is the major source of pulmonary surfactant in the lung. Our laboratory has recently demonstrated the feasibility of airway delivery of genetically engineered alveolar macrophages to the alveolar structures. We present preliminary data that indicate that freshly isolated type II cells can be intratracheally delivered to mice with bleomycin-induced acute lung injury. The donor type II cells can be easily identified and appear to attach to the alveolar wall surface. We propose that these type II cells will subsequently engraft to the alveolar surface; if successful, this may result in functional recovery of the alveolar structures. Furthermore, we have successfully transfected alveolar epithelial cells in vitro and demonstrated resistance to bleomycin-induced DNA damage and cell injury. These cells, referred to as "super type II cells", may represent a population of donor cells that will engraft more successfully than normal type II cells. Therefore, we hypothesize that: airway delivery of alveolar epithelial progenitor cells to the alveolar structures during bleomycin lung injury will result in engraftment and replacement of the injured alveolar epithelium and will hasten recovery of lung function. The specific aims of this proposal are: 1) to demonstrate that airway delivery of alveolar epithelial progenitor cells (type II cells, marrow-derived progenitor cells) will localize to the alveolar structures and engraft to the injured alveolar surface during bleomycin-induced acute lung injury, 2) to determine if successful engraftment of alveolar epithelial progenitor cells to the alveolar epithelium will hasten recovery from bleomycin-induced acute lung injury, and 3) to determine if donor type II cells transfected to be more resistant to bleomycin toxicity, i.e. "super type II cells", engraft more successfully and promote more rapid recovery than normal type II cells. If successful, this model of alveolar tissuegenesis will represent a highly novel therapeutic approach in repair of diffuse alveolar damage during acute lung injury.

描述（由申请人提供）： 急性肺损伤的特征是弥漫性肺泡损伤，伴有I型和II型肺泡上皮细胞的损伤和死亡。 对II型细胞的损伤是特别关键的，因为它是I型细胞的祖细胞，并且是肺中肺表面活性剂的主要来源。 我们的实验室最近证明了基因工程肺泡巨噬细胞的肺泡结构的气道输送的可行性。 我们目前的初步数据表明，新鲜分离的II型细胞可以通过气管内输送到博莱霉素诱导的急性肺损伤小鼠。 供体II型细胞可以很容易地识别，并似乎附着在肺泡壁表面。 我们建议，这些II型细胞将随后移植到肺泡表面，如果成功，这可能会导致肺泡结构的功能恢复。 此外，我们已经成功地在体外转染肺泡上皮细胞，并表现出对博莱霉素诱导的DNA损伤和细胞损伤的抗性。 这些细胞，称为“超级II型细胞”，可以代表比正常II型细胞更成功移植的供体细胞群体。 因此，我们假设：在博莱霉素肺损伤期间，肺泡上皮祖细胞向肺泡结构的气道递送将导致受损肺泡上皮的植入和替换，并将加速肺功能的恢复。 这项建议的具体目标是：1）证实肺泡上皮祖细胞的气道递送（II型细胞，骨髓来源的祖细胞）将定位于肺泡结构并在博来霉素诱导的急性肺损伤期间移植到受损的肺泡表面，2）为了确定肺泡上皮祖细胞成功植入肺泡上皮是否会加速从博来霉素的恢复，诱导的急性肺损伤，和3）确定被转染以对博来霉素毒性更有抗性的供体II型细胞，即“超级II型细胞”，是否比正常II型细胞更成功地植入并促进更快的恢复。 如果成功，这种肺泡组织发生模型将代表一种高度新颖的治疗方法，在急性肺损伤弥漫性肺泡损伤的修复。