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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL103868-01A1
Application #
8105273
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (02))
Program Officer
Eu, Jerry Pc
Project Start
2011-04-07
Project End
2016-02-29
Budget Start
2011-04-07
Budget End
2012-02-29
Support Year
1
Fiscal Year
2011
Total Cost
$427,500
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Parimon, Tanyalak; Chen, Peter (2017) ?6?4 Integrin Directs Alveolar Epithelial Migration. Am J Respir Cell Mol Biol 56:413-414
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Brauer, Rena; Chen, Peter (2016) Influenza leaves a TRAIL to pulmonary edema. J Clin Invest 126:1245-7
Brauer, Rena; Ge, Lingyin; Schlesinger, Saundra Y et al. (2016) Syndecan-1 Attenuates Lung Injury during Influenza Infection by Potentiating c-Met Signaling to Suppress Epithelial Apoptosis. Am J Respir Crit Care Med 194:333-44
Gharib, Sina A; Edelman, Jeffery D; Ge, Lingyin et al. (2015) Acute cellular rejection elicits distinct microRNA signatures in airway epithelium of lung transplant patients. Transplant Direct 1:
Grazioli, Serge; Gil, Sucheol; An, Dowon et al. (2015) CYR61 (CCN1) overexpression induces lung injury in mice. Am J Physiol Lung Cell Mol Physiol 308:L759-65

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