Developmental pathways regulating adult lung quiescence

调节成人肺静止的发育途径

基本信息

批准号：
9108646
负责人：
EDWARD E MORRISEY
金额：
$ 56.82万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2020-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9108646
关键词：
Address Adult Affect Architecture Basal cell carcinoma Binding Biochemical Cardiac Cardiopulmonary Cell Cycle Cell Lineage Cell Proliferation Cells Chronic Obstructive Airway Disease Complex Data Development Disease Endoderm Epithelial Equilibrium Erinaceidae Event Fibrosis Genetic Genetic Variation Growth Homeostasis Human Genetics In Vitro Injury Intervention Lead Ligands Lung Lung diseases Malignant Neoplasms Malignant neoplasm of lung Mediating Mesenchymal Molecular Morphogenesis Mutation Natural regeneration Organ Pathway interactions Play Population Predisposition Process Proliferating Pulmonary Fibrosis Regenerative response Regulatory Pathway Respiratory physiology Role SHH gene Schools Signal Pathway Signal Transduction Stem cells Stimulus Tissues cell injury human disease in vivo in vivo Model insight lung development medulloblastoma new therapeutic target novel organ growth paracrine progenitor public health relevance repaired response response to injury smoothened signaling pathway stem tumor

项目摘要

DESCRIPTION (provided by applicant): Tissues respond in different ways to injury to repair and regenerate lost cells and damaged architecture. The lung responds robustly to injury through activation of spatially restricted stem/progenitor cell populations and through re-entry of differentiated cells into the cell cycle. This robust response to injury stands in contrast to the normal homeostatic state, which is remarkably quiescent. One school of thought suggests that quiescence is a default state in many tissues resulting from lack of growth stimuli as demonstrated in culture conditions. However, this does not fully explain how cells remain quiescent within a complex microenvironment in vivo during tissue homeostasis. An alternative hypothesis is that quiescence is actively maintained through as yet unknown molecular pathways. Such an active process would be important for the delicate balance between cellular quiescence required for maintaining tissue integrity during normal homeostasis and the rapid regenerative response after injury. Such information is important given that disruption in this state could lead to re-activation of cell proliferation in an uncontrolled manner and may underlie several lung diseases including pulmonary fibrosis and cancer. The Hedgehog (Hh) pathway is a hallmark signaling pathway that coordinates epithelial-mesenchymal interactions during development in multiple organs including the lung, through paracrine activation of smoothened (Smo)-mediated downstream signaling events. Of the three known Hh ligands, sonic hedgehog (Shh) is the best understood, is highly expressed during lung development, and plays an essential role in lung morphogenesis. Despite its clear role in organ development, little is known about whether or how Hh signaling coordinates epithelial-mesenchymal interactions in the adult lung to maintain tissue homeostasis or modulate injury and regeneration. Hh signaling activity has been noted in the adult lung through expression of the downstream effector Gli1, along with studies suggesting hedgehog promotes mesenchymal proliferation in vitro. However, Hh's function in normal adult tissue quiescence or its role in injury and regeneration in the lung has not been examined in in vivo models. Our preliminary data suggest that Hh signaling is active in the adult lung and is used to maintain mesenchymal quiescence during normal homeostasis as well as after injury in the proximal airways. Thus, Hh signaling plays a critical role in maintainig lung quiescence and is important in the response of the lung to injury.

描述（适用提供）：组织以不同的方式响应损伤，以修复和再生损失的细胞和损坏的结构。肺部通过激活空间限制的茎/祖细胞群体以及通过重新输入而对伤害的反应强烈将细胞分化为细胞周期。这种对伤害的强大反应与正常的稳态状态相反，这是非常静止的。一所思想流派表明，由于缺乏生长刺激，在培养条件下证明，静止是许多组织中的默认状态。但是，这并不能完全解释组织稳态期间在体内复杂的微环境中如何保持细胞的静止。另一种假设是，通过尚未清楚的分子途径积极维持静止。这样的主动过程对于在正常稳态期间维持组织完整性所需的细胞静止与受伤后快速再生反应之间的微妙平衡至关重要。考虑到这种状态下的破坏可能导致细胞增殖以不受控制的方式重新激活，并且可能是几种肺部疾病（包括肺纤维化和癌症）的基础。刺猬（HH）途径是一种标志性信号通路，通过平滑（SMO）介导的下游信号事件的旁分泌激活在内的多个器官（包括肺）的发育过程中，在包括肺在内的多个器官的发育过程中协调上皮 - 间质相互作用。在三个已知的HH配体中，Sonic刺猬（SHH）是最好的理解，在肺发育过程中高度表达，并且在肺形态发生中起着至关重要的作用。尽管在器官发育中起着明显的作用，但对HH信号传导的辅助是在成年肺中的上皮 - 间质相互作用以维持组织稳态或调节损伤和再生的知之甚少。通过表达下游效应子Gli1的表达，在成年肺中已注意到HH信号传导活性，以及表明刺猬在体外促进间充质增殖的研究。但是，在体内模型中尚未检查HH在正常成人组织静止或其在肺部损伤中的作用和肺部再生的作用。我们的初步数据表明，HH信号在成年肺中有效，用于在正常稳态期间以及近端气道受伤后保持间充质静止。这是HH信号在维持肺静止中起关键作用，并且在肺对损伤的反应中很重要。