The lungs are constantly exposed to environmental toxins. Injured lung epithelium must quickly heal in order to re-establish the barrier between the body and outside world. A number of remodeling diseases are the result of aberrant repair (e.g., asthma remodeling, COPD, obliterative bronchiolitis, bronchiectasis). Therefore understanding the normal reparative process in the lungs is fundamental to understanding the mechanisms of disease pathogenesis. After injury, epithelial cells migrate over the wounded surfaces by a coordinated response between the cell and matrix. The lung epithelium utilizes syndecan-1 in modulating the cell-matrix interaction. By functionally coupling itself to the a2?1 integrin, syndecan-1 tunes the cell adhesiveness to collagen thereby allowing efficient cell migration to occur. Preliminary data suggests that syndecan-1 is regulating the affinity state of the a2?1 integrin through a direct interaction of the ectodomain of these proteins. Additionally, changes in the integrin conformational state controls cell migration speed by altering focal adhesion dynamics. The goal of this proposal is to determine the mechanisms by which syndecan-1 regulates the activation state of the a2?1 integrin thereby modulating cell migration via changes to focal adhesion dynamics. These studies will be performed with cell lines, organotypic lung epithelial cultures and in vivo models of repair.
Aim 1 will map the specific sequence of the syndecan-1 core protein needed to interact with the a2?1 integrin and identify additional binding partners in the syndecan-1 and a2?1 integrin complex.
Aim 2 will focus on identifying mechanisms by which syndecan-1 regulates the 1221 integrin afinity state.
Aim 3 will determine how syndecan-1 effects on a2?1 integrin afinity regulates focal adhesion dynamics and traction forces in migrating cells. These studies will better define the mechanisms by which syndecan-1 regulates cell migration through a2?1 integrin activation and potentially identify ways to manipulate this interaction to modulate lung repair.
Pathological conditions (e.g., tumor invasion and metastasis, chronic inflammation, fibrosis) arise when the epithelium either cannot repair or lose the contextual control that shuts down the migration process. Therefore, understanding the basic mechanisms that control the epithelial cell migration in health will complement our understanding of pathological states. The relevance of this project will be to identify mechanisms that facilitate lung repair after injury and opens up the possibility to develop therapeutic strategies to augment healing and prevent infectious and pathologic consequences of aberrant wound healing.
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