Bronchioalveolar Stem Cells Contribute to Alveolar Repair in Emphysema

描述（由申请人提供）：COPD是一个日益严重的全球性问题。迄今为止，大多数研究都集中在空域炎症和破坏的机制上。据推测，修复是不够的，但修复的机制，特别是细胞修复，还没有得到解决。该提案将支持主要研究者对最近描述的肺中称为支气管肺泡干细胞（BASC）的成体干细胞群进行研究。BASCs具有气道上皮细胞和肺泡上皮细胞的特性。它们已被证明在气道和肺泡细胞损伤模型中增殖，并可能有助于气道和肺泡修复。我们的总体假设是，BASCs是肺泡维护和BASCs的失败，以修复受损的肺泡吸烟者有助于肺气肿。此外，BASCs使用它们的MMPs（特别是MMP-9）库来重新填充肺泡上皮和基底膜。为了解决这个假设，我们提出：（1）应用转基因谱系标记的BA$Cs来解决BASCs迁移到肺泡空间中代替肺气肿模型中的肺泡I型和II型细胞的假设。我们将使用我们实验室开发的谱系标记小鼠（CC 10-CreXRosa 26报告小鼠）来评估BASC对实质中两种细胞类型的贡献。(2)产生转基因BASC谱系消融小鼠以评估BASC促进肺泡结构修复的能力。我们将通过产生转基因CC 10-CreXSPCLox-STOP-Lox-TK小鼠来产生BASC缺陷型小鼠，其中BASC（即CC-10+和SPC+）将用更昔洛韦治疗特异性缺失。(3)评估MMP-9在肺气肿模型中BASC迁移和肺泡维持中的作用。我们将使用野生型和MMP-9缺陷小鼠（在我们的实验室中产生）和从它们分离的BASC细胞来评估MMP-9在BASC细胞迁移中的作用。职业目标：这个建议和教学学习将允许P.I.发展专业和技术技能，成为一名多产的独立科学家。肺干细胞生物学和肺气肿修复的科学重点代表了对公共卫生具有重要意义的长期职业重点。值得注意的是，学习如何创建新的转基因工具将对肺部科学界特别重要。相关性（见说明）：COPD是一种由慢性吸入香烟烟雾引起的疾病，在世界范围内流行，预计到2020年将成为第三大死亡原因。迄今为止，我们还没有将我们对发病机制的理解转化为疾病修饰疗法的发展。此外，关闭炎症性、破坏性过程只能防止肺进一步恶化，但不能恢复肺功能。为了恢复肺功能，我们解决了肺气肿的修复过程及其失败的基础。 (End摘要）

DESCRIPTION (provided by applicant): COPD Is a growing problem worldwide. Most research to date has focused on the mechanisms of airspace inflammation and destruction. It has been presumed that repair is insufficient, but the mechanisms of repair, particularly cellular repair, have not been addressed. This proposal will support the Principle Investigator in the study of a recently described population of adult stem cells in the lung termed bronchioalveolar stem cells (BASCs). BASCs possess properties of both airway and alveolar epithelial cells. They have been shown to proliferate in airway and alveolar cell injury models and may contribute to both airway and alveolar repair. Our overall hypothesis is that BASCs are essential for alveolar maintenance and failure of BASCs to repair damaged alveoli in smokers contributes to emphysema. Moreover, BASCs use their repertoire of MMPs, particularly MMP-9, to repopulate the alveolar epithelium and basement membrane To address this hypotheses we propose to: (1) Apply transgenic lineage tagged BA$Cs to address the hypothesis that BASCs migrate into the alveolar space replacing alveolar type I and II cells in models of emphysema. We will use lineage tagged mice (CC10-CreXRosa 26 reporter mice) developed in our lab to evaluate BASC contribution to both cells types in the parenchyma. (2) Generate transgenic BASC lineage ablated mice to evaluate BASC ability to promote alveolar structural repair. We will generate a BASC deficient mouse by generating a transgenic CC10-CreXSPCLox-STOP-Lox-TK mouse in which BASCs, (that are CC-10+ and SPC+), will be specifically deleted with gancyclovir treatment. (3) Evaluate the role that MMP-9 plays in BASC migration and alveolar maintenance in models of emphysema. We will use wild type and MMP-9 deficient mice (generated in our lab) and BASC cells isolated from them to evaluate the role of MMP-9 in migration of BASC cells. Career Goals: This proposal and didactic learning will allow the P.I. to develop professional and technical skills to become a productive independent scientist. The scientific focus of lung stem cell biology and repair in emphysema represents a long-term career focus of significant importance to public health. Of note, learning how to create new transgenic tools will be of particular importance to the lung scientific community. RELEVANCE (See Instructions): COPD is a disease caused by the chronic inhalation of cigarette smoke which is epidemic worldwide, and predicted to be 3rd leading cause of death by 2020. To date, we have yet to translate our understanding of the pathogenesis into the development of disease modifying therapy. In addition, turning off the inflammatory, destructive processes can only prevent further lung deterioration but not restore lung function. In order to restore lung function, we address the process of repair and the basis for its failure in emphysema. (End of Abstract)