Defining the stromal contribution to the aging niche in the lung

定义基质对肺部衰老生态位的贡献

基本信息

批准号：
9754719
负责人：
Nabora Soledad Reyes de Barboza
金额：
$ 5.93万
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：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2020-06-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754719
关键词：
Adult Affect Age Age-Years Aging Air Alveolar Alveolar Cell Alveolus Area Automobile Driving Biological Biological Assay Cell Aging Cell physiology Cells Chronic Coculture Techniques Data Development Disease Distal Elderly Exhibits Feedback Functional disorder Gases Human In Vitro Life Cycle Stages Light Link Lung Lung diseases Maintenance Mediating Mendelian disorder Modeling Molecular Mus Mutant Strains Mice Mutation Organ Organism Organoids Pathogenesis Pathologic Phase Phenocopy Phenotype Physiological Play Population Premature aging syndrome Process Progeria Pulmonary Emphysema Reporting Reproduction Research Respiratory physiology Risk Risk Factors Role Stem cells Stromal Cells Structure Surface Syndrome Testing Tissues age related aged alveolar homeostasis causal variant cell type insight loss of function mouse model mutant normal aging premature progenitor respiratory spatiotemporal stromal progenitor therapeutic target transcriptome

项目摘要

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.

项目摘要：该项目旨在了解超出表型后果的肺部衰老过程。在这两个中人和小鼠，老年肺中气体交换表面积的损失反映了肺气肿的损失。这与肺部年龄相关的功能丧失涉及的特定细胞尚不清楚。此外，目前尚不清楚是否单个或多个细胞类型有助于衰老过程。在肺部肺部和祖细胞中嵌入基质中。基质细胞提供支持，结构和功能维护周围的细胞。在这个项目中，我们试图定义对肺泡干细胞的基质反馈老年肺。我们使用罕见的，单基因过早衰老的诱导小鼠模型称为 Hutchinson-Gilford Progeria综合征（HGP），以识别特定的细胞过程或潜在过程有助于衰老表型。 HGPS突变小鼠的肺揭示了肺泡气体交换表面积的损失和空气增加空间。我们能够通过调节肺部远端基质的功能来表达衰老表型，因此暗示了基质在维持肺泡稳态中的作用。我们建议调查肺基质作为特定细胞类型的潜在利基市场，该细胞类型会产生牙槽茎的老化微环境细胞。首先，我们将确定过早老化的基质如何影响体外的肺泡祖细胞共培养分析。与诱导疾病一起空间激活HGP，我们将测试基质的潜力过早年龄。