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

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

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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.

项目摘要许多严重的呼吸道疾病会导致气体交换问题，这是肺。其中一些突然发作，例如严重的肺炎肺损伤，而另一些则发育在长时间的长时间内，例如COPD和特发性肺纤维化（IPF）。有证据表明慢性呼吸衰竭形式是由于失去肺部能够维持自己的能力而导致的，部分原因是由于常规肺部干细胞的功能障碍，通常会执行此作用。因此，发现肺部干细胞在整个生命中受调节的特定分子和细胞机制可能是有助于了解COPD和IPF的发展方式。实现对肺的深刻理解干细胞调节可能会改善预测，诊断甚至药理治疗的策略这样的疾病。此外，鉴于通过医疗支气管镜检查肺的易于访问性，这是理想的可以通过提供健康干细胞的靶向器官，从而阻止疾病进展甚至产生如果可以成功将它们移植到患病的肺部，则改进。我们发现其中一个气体交换区域的功能细胞，肺泡II型（AT2）细胞，充当小鼠肺的干细胞在整个生命周期中，并确定了调节其活性的几个因素。该提议的目的是通过研究当地环境来扩展我们对这些干细胞如何调节这些干细胞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特定和不同方面，包括如何诱导其增殖产生新细胞，如何达到响应伤害的瞬时调节能力，以及是否存在调节环境比干细胞本身更重要，以维持肺部寿命。我们的发现将大大加深我们对这些肺干细胞的理解故意操纵以生成适合细胞移植或通过药理的大量为治疗性“重新增长”进行活动。