Defining the stromal contribution to the aging niche in the lung

项目摘要： 该项目旨在了解表型后果之外的肺老化过程。无论是 人和小鼠，老年肺中气体交换表面积的损失反映了肺气肿。的 与肺年龄相关的功能丧失有关的具体细胞还不清楚。此外，尚不清楚是否 单个或多个细胞类型有助于老化过程。在肺远端，肺泡和祖细胞 嵌入基质中。间质细胞提供支持，结构和功能维持， 周围的细胞。在这个项目中，我们试图定义间质反馈肺泡干细胞在过早 老肺我们使用一种罕见的单基因早衰症的诱导小鼠模型， Hutchinson-Gilford早衰综合征（HGPS），以确定特定的细胞过程或潜在的过程 导致衰老的表型。 HGPS突变小鼠的肺显示肺泡气体交换表面积减少， 空间我们能够通过调节肺远端基质的功能来复制衰老表型， 从而暗示了基质在维持肺泡内环境稳定中的作用。我们建议检查肺部 基质作为特定细胞类型的潜在小生境，为肺泡干细胞创造老化微环境 细胞首先，我们将在体外实验中确定过早老化的基质是如何影响肺泡祖细胞的。 共培养测定。使用诱导性疾病时空激活HGPS，然后我们将测试 间质使肺过早老化的可能性。

Project Summary: This project aims to understand the aging process in the lung beyond the phenotypic consequences. In both human and mouse, the loss of gas exchange surface area in aged lungs mirrors that of emphysema. The specific cells involved in the lung age-related loss of function are not well known. Additionally, it is unclear if single or multiple cell types contribute to the aging process. In the distal lung the alveoli and progenitor cells are embedded within the stroma. Stromal cells provide support, structure, and functional maintenance of surrounding cells. In this project we seek to define the stromal feedback to alveolar stem cells in prematurely aged lungs. We use the inducible mouse model of a rare, monogenic premature aging disease called Hutchinson-Gilford progeria syndrome (HGPS) to identify the specific cellular process or potential processes contributing to the aging phenotype. The lungs of HGPS mutant mice reveal a loss of alveolar gas exchange surface area and an increase in air space. We are able to phenocopy the aging phenotype by modulating the function of distal stroma in the lungs, thus implicating the role of the stroma in maintaining alveolar homeostasis. We propose to investigate the lung stroma as a potential niche for a specific cell type that creates an aging microenvironment for alveolar stem cells. First, we will determine how the prematurely aged stroma affects alveolar progenitor cells in an in vitro co-culture assay. Using with the inducible disease to spatiotemporally activate the HGPS we will then test the potential of the stroma to prematurely age the lungs.