Regenerative Role of Integrin Beta4pos p63pos Distal Lung Stem/Progenitor Cells

整合素 Beta4pos p63pos 远端肺干细胞/祖细胞的再生作用

基本信息

批准号：
8717289
负责人：
Andrew Vaughan
金额：
$ 5.51万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8717289
关键词：
Address Adopted Alveolar Alveolar Cell Alveolus Appearance Basal Cell Biological Process Bleomycin Cell model Cells Chronic Chronic lung disease Clara cell Critical Illness Cytokeratin Data Dependence Development Disease Distal Epithelial Epithelium Fibrosis Future Gases Gene Expression Profile Goals Homeostasis Human Image In Vitro Individual Influenza Inherited Injury Integrins Knowledge Lung Maintenance Messenger RNA Modeling Molecular Molecular Biology Techniques Mus Natural regeneration Organ Pathway interactions Patients Phenotype Population Process Pulmonary Surfactant-Associated Protein C Recovery Reporting Resolution Role Signal Pathway Site Slice Small Interfering RNA Source Stem cells Structure of parenchyma of lung Testing Therapeutic Time Tissues Trachea Transgenic Mice Type II Epithelial Receptor Cell Ursidae Family Work alveolar epithelium alveolar type II cell base cell motility cell type fibrogenesis in vivo injured insight lung imaging lung injury lung regeneration prevent progenitor public health relevance regenerative repaired research study response stem unpublished works

项目摘要

DESCRIPTION (provided by applicant): The epithelium of the distal lung performs critical biological functions including gas exchange and providing a barrier to prevent access of deleterious airborne agents into the body. It is also the target of numerous inherited and acquired diseases, represented by over 10% of the US population suffering from chronic lung disease. Despite the importance of this tissue, there is considerable disagreement as to the cell types important for the maintenance and repair of this organ. In the trachea, basal cells are the key progenitor cell type, while clara cells are thought to be more important progenitors in distal airways, especially in mice which lack basal cells outside the trachea. Alveolar type II cells have been long established as an important progenitor population for alveoli, a paradigm repeatedly confirmed in recent studies. In addition, several groups have identified cells that bear no mature lineage markers as potential progenitors for alveolar cell types. Specifically, distal lung integri ¿4-expressing cells are proposed to contribute to alveolar repair after bleomycin-induced injury, while cytokeratin 5(Krt5)/p63-expressing cells have been implicated in alveolar regeneration after influenza infection. Our unpublished work demonstrates that abundant Krt5pos cells also appear after bleomycin injury, and in both injury models these cells strongly express ¿4. Further characterization of freshly isolated ¿4+ cells from uninjured lungs revealed that these cells express p63, but not Krt5. However, upon expansion ex vivo, Krt5 is upregulated, demonstrating the propensity of these cells to adopt a basal cell-like phenotype. The major goal of this proposal is to determine whether these distal p63+ ¿4+ are in fact the cell-of-origin for expanded post-injury Krt5+ cells and to define the extent to which these cells are responsible for alveolar repair / regeneration. We will address this hypothesis with the following Specific Aims: 1) Determine the in vivo activation response of ¿4+ p63+ cells to lung injury. 2) Test whether regulated expression of p63 is critical to the acquisition of a Krt5+ regenerative phenotype by distal lung ¿4+Krt5+ cells. Several strains of transgenic mice, lung slice culture imaging, and in vitro molecular biology techniques will be used to address these aims experimentally. These studies will result in a better understanding of how lung epithelium responds to injury and will provide insights as to how lung progenitors might be exploited / directed towards therapeutic purposes.

描述（由申请人提供）：远端肺的上皮执行重要的生物功能，包括气体交换和提供屏障以防止有害的空气传播物质进入体内。它也是许多遗传性和获得性疾病的目标，以过度感染为代表。 10% 的美国人患有慢性肺部疾病，尽管该组织很重要，但对于维持和修复该器官的重要细胞类型存在很大分歧。在气管中，基底细胞是关键的祖细胞。细胞类型，而克拉拉细胞被认为是远端气道中更重要的祖细胞，尤其是在气管外缺乏基底细胞的小鼠中。早已被确定为肺泡的重要祖细胞群，这是最近研究中反复证实的范例。此外，一些研究小组已经鉴定出不具有成熟谱系标记的细胞作为肺泡细胞类型的潜在祖细胞。表达 4 的细胞被认为有助于博来霉素诱导的损伤后的肺泡修复，而表达细胞角蛋白 5 (Krt5)/p63 的细胞与流感感染后的肺泡再生有关。我们未发表的工作表明，博来霉素后也会出现大量的 Krt5pos 细胞。损伤，并且在两种损伤模型中这些细胞强烈表达 ¿ 4. 新鲜分离的进一步表征 ¿来自未受伤肺部的 4+ 细胞显示这些细胞表达 p63，但不表达 Krt5。然而，在离体扩增后，Krt5 上调，证明这些细胞倾向于采用基底细胞样表型。该提议的主要目标是。以确定这些远端 p63+ ¿ 4+ 实际上是损伤后扩增的 Krt5+ 细胞的起源细胞，并确定这些细胞负责肺泡修复/再生的程度。我们将通过以下具体目标来解决这一假设：1) 确定的体内激活反应4+ p63+ 细胞对肺损伤 2) 测试 p63 的调节表达是否对于远端肺获得 Krt5+ 再生表型至关重要。 4+Krt5+ 细胞。几种转基因小鼠品系、肺切片培养成像和体外分子生物学技术将用于通过实验实现这些目标。这些研究将有助于更好地了解肺上皮如何响应损伤，并提供见解。关于如何利用/引导肺祖细胞达到治疗目的。