Identifying niche factors regulating distinct properties of AT2 stem cells

识别调节 AT2 干细胞独特特性的生态位因子

基本信息

批准号：
9576667
负责人：
Tushar Jasubhai DESAI
金额：
$ 56.28万
依托单位：
STANFORD UNIVERSITY
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：
2018-08-22 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9576667
关键词：
Ablation Acute Adult Respiratory Distress Syndrome Aging Alveolar Automobile Driving Binding Biochemistry Bronchoscopy Cell Death Cell Proliferation Cell Transplantation Cell division Cells Chronic Chronic Obstructive Airway Disease Cues Data Diagnosis Disease Disease Progression Elderly Environment Epidermal Growth Factor Receptor Epithelial Epithelial Cells Failure Fibroblasts Fostering Functional disorder Gases Goals Growth Human Immune Injury Integrins Knowledge Lead Learning Life Ligands Longevity Lung Lung Capacity Lung diseases Maintenance Maps Medical Minor Mitogens Modeling Molecular Morbidity - disease rate Mus Natural regeneration Organ Paracrine Communication Pathology Patients Pharmacology Pneumonia Population Production Proliferating Property RNA Regulation Research Resolution Respiratory Failure Respiratory physiology Role Signal Pathway Signal Transduction Signaling Molecule Site Smoking Stem cells Surface Testing Therapeutic Time Tissues Transplantation WNT Signaling Pathway Work alveolar type II cell autocrine base cell behavior cell injury dimer idiopathic pulmonary fibrosis improved in vivo injured lung injury lung regeneration mortality new technology novel paracrine prevent programs receptor reconstitution repaired resilience response response to injury single cell analysis single cell technology stem cell biology therapeutic development

项目摘要

PROJECT SUMMARY A number of serious respiratory diseases cause problems with gas exchange, which is the principal function of the lungs. Some of these are sudden in onset, like lung injury from a severe pneumonia, while others develop over long periods of time, like COPD and Idiopathic Pulmonary Fibrosis (IPF). There is some evidence that the chronic forms of respiratory failure result from loss of the capacity of the lungs to maintain themselves, in part due to dysfunction of resident lung stem cells that normally perform this role. Therefore, discovering the specific molecular and cellular mechanisms by which lung stem cells are regulated throughout life may be helpful for understanding how COPD and IPF develop. Achieving this deep level of understanding about lung stem cell regulation may lead to improved strategies to predict, diagnose, and even pharmacologically treat such diseases. Furthermore, given the easy accessibility of the lung via medical bronchoscopy, it is an ideal organ to target with the delivery of healthy stem cells that might prevent disease progression or even produce improvement if they can be successfully transplanted into diseased lungs. We have found that one of the functional cells in the gas exchange region, the alveolar type II (AT2) cell, acts as a stem cell for mouse lung throughout the lifespan, and identified several factors that regulate its activity. The AIMS of this proposal are to expand our understanding of how these stem cells are regulated by studying the local environment that provides the signals that control their activity, including proliferation and differentiation. We will investigate three specific and distinct aspects of the stem cell behavior, including how it is induced to proliferate to generate new cells, how it attains the capacity to transiently regulate itself in response to injury, and whether the regulatory environment is as or more important than the stem cell itself for maintaining the lungs over the lifespan. Our findings will significantly deepen our understanding of precisely how these lung stem cells can be deliberately manipulated to generate large numbers suitable for cell transplantation, or by pharmacologically driving their activity for therapeutic 're-growth' purposes.

项目概要许多严重的呼吸系统疾病会导致气体交换出现问题，而气体交换是呼吸系统的主要功能。肺部。其中一些是突然发作的，例如严重肺炎导致的肺损伤，而另一些则是发展而来长期患病，如慢性阻塞性肺病 (COPD) 和特发性肺纤维化 (IPF)。有一些证据表明慢性呼吸衰竭的部分原因是肺部自我维持能力丧失由于通常执行此功能的常驻肺干细胞功能障碍。因此，发现肺干细胞在整个生命过程中受到调节的特定分子和细胞机制可能是有助于了解 COPD 和 IPF 的发展过程。实现对肺的深入了解干细胞调节可能会导致预测、诊断甚至药物治疗策略的改进此类疾病。此外，鉴于通过医用支气管镜可以轻松到达肺部，它是一种理想的选择输送健康干细胞的目标器官可能会阻止疾病进展，甚至产生如果它们能够成功移植到患病的肺部，情况就会有所改善。我们发现其中之一气体交换区域的功能细胞，即肺泡 II 型 (AT2) 细胞，充当小鼠肺的干细胞整个生命周期，并确定了调节其活动的几个因素。该提案的目的是通过研究当地环境来扩大我们对这些干细胞如何调节的理解提供控制其活动的信号，包括增殖和分化。我们将调查干细胞行为的三个具体且不同的方面，包括如何诱导其增殖产生新细胞，它如何获得短暂调节自身以响应损伤的能力，以及是否对于维持肺部的正常运转而言，调节环境与干细胞本身一样重要或更重要。寿命。我们的研究结果将显着加深我们对这些肺干细胞究竟如何发挥作用的理解。故意操纵以产生大量适合细胞移植的细胞，或通过药理学驱动他们的活动以达到治疗“再生长”的目的。