A clonal analysis of smooth muscle development in the mouse lung

小鼠肺平滑肌发育的克隆分析

• 批准号: 7446776
• 负责人: Maya Elise Kumar
• 金额: $ 5.29万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446776
• 关键词: Affect; Alveolus; Apoptosis; Asthma; Cell Migration Induction; Cells; Constriction procedure; Defect; Development; Diagnosis; Disease; Embryonic Development; Event; Extrinsic asthma; Fetal Development; Gases; Genetic Recombination; Hypertrophy; Image; Imagery; Individual; Label; Lead; Life; Lung; Mediating; Methods; Modeling; Mus; Muscle Development; Organ; Organ Culture Techniques; Pathogenesis; Pattern; Play; Predisposition; Process; Resolution; Respiratory physiology; Role; Running; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Specific qualifier value; Stem cells; Techniques; Time; Tissues; To specify; Tube; Uncertainty; airway hyperresponsiveness; airway remodeling; base; cell behavior; disease phenotype; lung development; mast cell; muscle hypertrophy; mutant; postnatal; progenitor; research study; respiratory smooth muscle

DESCRIPTION (provided by applicant): Summary: During embryonic development the conducting airways of the lung are wrapped in a layer of contractile smooth muscle that maintains tone and regulates dilation and constriction of the tubes. Misregulation and hypertrophy of the airway smooth muscle is a key feature of serious diseases affecting the lung in postnatal life including asthma. Signals originating in the airway smooth muscle play an essential role in airway remodeling and mast cell invasion, resulting in the airway hyperresponsiveness observed in allergic asthma. A predisposition to asthma is associated with patterning defects that arise during fetal development, highlighting the need to understand the normal process of smooth muscle development at a cellular resolution to provide a framework for understanding mutant phenotypes and disease pathogenesis. The development and patterning of the airway smooth muscle is essential for proper lung function, yet little is known about the cell progenitors of this tissue, their developmental potential how they assemble into smooth muscle during development. Using conditional Cre-mediated recombination techniques to fluorescently mark single cells at defined times during lung development and follow the fate of their progeny, the experiments detailed in this proposal will identify when and where progenitor cells are specified to form airway smooth muscle, and will define the developmental potential of those smooth muscle progenitors. This clonal labeling technique will then be extended to lung organ explants, which will allow visualization of the marking event and continual tracking of the marked cell and its progeny during development in culture. These experiments will provide a cellular level understanding of how airway smooth muscle is formed, an understanding that I hope will lead in the long run to new avenues for diagnosis and treatment of asthma and other disease affecting smooth muscle lineages of the lung. Relevance: The cellular basis for airway smooth muscle hypertrophy in allergic asthma is not completely understood. Doubt has been cast on whether proliferation alone is responsible for the expansion of the smooth muscle layer, and other factors such as cell migration, induction, and decreased apoptosis may play key roles in airway remodeling. In addition to providing a clear understanding of the process of normal smooth muscle development, the techniques detailed in this proposal can be extended to define the cellular events responsible for airway remodeling in asthma models, thereby opening new avenues for the diagnosis and treatment of the disease.

概述：在胚胎发育过程中，肺的传导气道被一层可收缩的平滑肌包裹，平滑肌维持张力并调节气管的扩张和收缩。气道平滑肌的失调和肥大是影响出生后肺部的严重疾病的一个关键特征，包括哮喘。源自气道平滑肌的信号在气道重塑和肥大细胞侵袭中发挥重要作用，导致过敏性哮喘气道高反应性。哮喘易感性与胎儿发育过程中出现的模式缺陷有关，强调需要在细胞分辨率上了解平滑肌发育的正常过程，以提供理解突变表型和疾病发病机制的框架。气道平滑肌的发育和模式对正常的肺功能至关重要，但对该组织的细胞祖细胞及其发育潜力知之甚少，它们如何在发育过程中组装成平滑肌。利用条件cre介导的重组技术，在肺发育的特定时间荧光标记单个细胞，并跟踪其后代的命运，本提议中详细的实验将确定祖细胞何时何地被指定形成气道平滑肌，并将确定这些平滑肌祖细胞的发育潜力。这种克隆标记技术将扩展到肺器官外植体，这将使标记事件可视化，并在培养过程中对标记细胞及其后代进行持续跟踪。这些实验将从细胞水平上了解气道平滑肌是如何形成的，我希望从长远来看，这种理解将为哮喘和其他影响肺平滑肌谱系的疾病的诊断和治疗提供新的途径。