Molecular transduction of the mechanical environment in airway epithelium

Project: Research project

Project Details

Description

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.
StatusNot started

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