Transduction of the environment in airway epithelium

描述(申请人提供)：机械环境深刻地影响肺的结构和功能，从发育中的肺的分支形态发生和细胞分化，到成熟器官的生长、损伤和重塑。细胞感知和响应机械环境的潜在分子机制仍然难以捉摸。新近的证据表明，分隔呼吸道上皮细胞的细胞间隙在生理负荷下是高度变形的。这些细胞间隙是涉及表皮生长因子受体(EGFR)及其配体的假定自分泌信号环的位置。生理水平的机械应力作用于呼吸道上皮细胞，无论是在体外还是在原位，都通过EGFR途径触发信号。综合这些观察结果，得出以下中心假设：机械应力可以通过在动态调节的细胞间隙中运行的自分泌EGFR环的稳态活动来传递。这一假说将利用原代人类呼吸道上皮细胞培养在以下三个特定目标中得到验证：(1)建立上皮细胞间隙自分泌信号环的分子组成和构成功能；(2)确定细胞间隙对生理相关负荷条件的动态生物物理反应；(3)使用生化和计算工具来检验中心假说，然后探索其在调节粘液分泌表型的表达中的生物学作用。粘液SAC是各种呼吸道疾病中上调的粘液分泌表型的标志。由此产生的见解可能会为发生在细胞外空间的机械转导建立一个新的、意想不到的范式，并改变我们对机械力如何在健康和疾病中对呼吸道生物学做出贡献的观点。肺在正常(如呼吸)和疾病(如哮喘)条件下会经历一系列的机械力，影响肺的结构和功能。这项拟议的研究将探索排列在呼吸道内的细胞如何感知和响应机械环境的变化。这些研究将为理解和调节肺部的机械反应提供一个框架。

DESCRIPTION (provided by applicant): The mechanical environment profoundly influences the structure and function of the lung, from branching morphogenesis and cellular differentiation in the developing lung, to growth, injury, and remodeling of the mature organ. The underlying molecular mechanisms by which cells sense and respond to their mechanical environment remain elusive. Recently obtained evidence demonstrates that the intercellular spaces separating airway epithelial cells are highly deformable under physiological loads. These intercellular spaces are the site of putative autocrine signaling loops involving the epidermal growth factor receptor (EGFR) and its ligands. Physiological levels of mechanical stress applied to airway epithelial cells, both in vitro and in situ, trigger signaling through the EGFR pathway. Integration of these observations leads to the following central hypothesis: mechanical stress can be transduced through the steady-state activity of an autocrine EGFR loop operating in a dynamically regulated intercellular space. This hypothesis will be tested in the following three specific aims using primary human airway epithelial cultures: (1) establish the molecular components and constitutive functionality of the autocrine signaling loop in the epithelial intercellular space; (2) define the dynamic biophysical response of the intercellular space to physiologically relevant loading conditions; and (3) use biochemical and computational tools to test the central hypothesis, then explore its biological role in modulating the expression of mucSAC, a marker of the mucus secretory phenotype upregulated in various airway disorders. The resulting insights could establish a new and unanticipated paradigm for mechanotransduction occurring in the extracellular space, and change our view of how mechanical forces contribute to the biology of the airways in health and disease. The lung experiences a range of mechanical forces during normal (e.g. breathing) and disease (e.g. asthma) conditions, influencing lung structure and function. The proposed studies will explore how the cells that line the airways sense and respond to changes in their mechanical environment. These studies will provide a framework for understanding and modulating mechanical responses in the lung.