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: 7630465
• 负责人: Maya Elise Kumar
• 金额: $ 5.53万
• 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/7630465
• 关键词: Affect; Alveolus; Apoptosis; Asthma; Cell Migration Induction; Cells; 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; constriction; disease phenotype; lung development; mast cell; meetings; 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.

描述（由申请人提供）： 摘要：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，该平滑肌可维持张力并调节管的扩张和收缩。气道平滑肌的失调和肥大是产后影响肺部的严重疾病（包括哮喘）的一个关键特征。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，导致过敏性哮喘中观察到的气道高反应性。哮喘易感性与胎儿发育过程中出现的模式缺陷有关，这突出表明需要在细胞分辨率上了解平滑肌发育的正常过程，以便为理解突变表型和疾病发病机制提供框架。气道平滑肌的发育和模式对于正常的肺功能至关重要，但人们对这种组织的细胞祖细胞以及它们在发育过程中如何组装成平滑肌的发育潜力知之甚少。使用条件Cre介导的重组技术，在肺发育过程中的特定时间对单细胞进行荧光标记，并追踪其后代的命运，该提案中详述的实验将确定祖细胞被指定形成气道平滑肌的时间和地点，并将确定这些平滑肌祖细胞的发育潜力。然后，这种克隆标记技术将扩展到肺器官外植体，这将允许标记事件的可视化，并在培养过程中持续跟踪标记的细胞及其后代。这些实验将提供对气道平滑肌如何形成的细胞水平理解，我希望这种理解从长远来看将为诊断和治疗哮喘和影响肺部平滑肌谱系的其他疾病提供新途径。 相关性：过敏性哮喘气道平滑肌肥大的细胞基础尚不完全清楚。人们怀疑增殖是否单独导致了平滑肌层的扩张，而细胞迁移、诱导和细胞凋亡减少等其他因素可能在气道重塑中发挥着关键作用。除了提供对正常平滑肌发育过程的清晰理解之外，该提案中详述的技术还可以扩展以定义负责哮喘模型中气道重塑的细胞事件，从而为该疾病的诊断和治疗开辟新途径。