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

• 批准号: 10178079
• 负责人: Tushar Jasubhai DESAI
• 金额: $ 53.58万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-22 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178079
• 关键词: 3-Dimensional; 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; EGF gene; 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; Organ; Paracrine Communication; Pathology; Patients; Pharmacology; Pneumonia; Population; Production; Proliferating; Property; RNA; Regulation; Research; Resolution; Respiratory Failure; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Smoking; Surface; Testing; Therapeutic; Time; Tissues; Transplantation; WNT Signaling Pathway; Work; alveolar epithelium; alveolar type II cell; autocrine; base; cell behavior; cell injury; dimer; epithelial injury; epithelium regeneration; idiopathic pulmonary fibrosis; improved; in vivo; lung injury; lung regeneration; mortality; new technology; novel; paracrine; prevent; programs; pulmonary function; receptor; reconstitution; repaired; resilience; response; response to injury; single cell analysis; single cell technology; stem cell biology; stem cells; therapeutic development

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，例如严重肺炎造成的肺损伤，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检查可以轻松到达肺部，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。

项目成果

KRAS(G12D) drives lepidic adenocarcinoma through stem-cell reprogramming.

• DOI: 10.1038/s41586-023-06324-w
• 发表时间: 2023-07
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Juul, Nicholas H.;Yoon, Jung-Ki;Martinez, Marina C.;Rishi, Neha;Kazadaeva, Yana I.;Morri, Maurizio;Neff, Norma F.;Trope, Winston L.;Shrager, Joseph B.;Sinha, Rahul;Desai, Tushar J.
• 通讯作者: Desai, Tushar J.

Advances in Proximity Ligation in situ Hybridization (PLISH).

邻近连接原位杂交 (PLISH) 的进展。

• DOI: 10.21769/bioprotoc.3808
• 发表时间: 2020
• 期刊: Bio-protocol
• 影响因子: 0.8
• 作者: Nagendran,Monica;Andruska,AdamM;Harbury,PehrB;Desai,TusharJ
• 通讯作者: Desai,TusharJ