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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过早衰老疾病的诱导型小鼠模型，称为 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。