The career goal of this proposal is to become an independent investigator in the field of Pulmonary and Critical Care Medicine. This award describes an integrated curriculum combining didactic coursework with a research program sponsored by David Madtes, M.D., an expert in the field of tissue inhibitors of metalloproteinases (TIMPs), and co-sponsored by William Parks, Ph.D., an expert in the field of matrix metalloproteinases (MMPs). Obliterative bronchiolitis (OB) is the pathological hallmark of chronic lung transplant rejection with high mortality and ineffective treatments. The pathogenesis of OB is largely unknown, but studies show that disease development is linked to destruction of the airway epithelium. Matrilysin (MMP-7) is necessary for airway epithelial repair, and its proteolytic activity in vitro is inhibited by TIMP-1. Therefore, it is reasonable to speculate that TIMP-1 serves a regulatory role in epithelial repair by silencing MMP-7 activity. In a murine model of OB, we have found that TIMP-1 expression is increased in allogeneic trachea! transplants and is localized to the a I log raft epithelium during the period of epithelial repair. Furthermore, and supporting the idea that TIMP-1 contributes to disease progression, allogeneic tracheas using TIMP-1 deficient donors or recipients had decreased luminal obliteration and more complete epithelial repair compared to those transplanted into wild-type recipients. In contrast, isografts from matrilysin deficient mice showed sustained epithelial damage and submucosal inflammation unlike wild-type isografts. Therefore, my central hypothesis is that TIMP-1 attenuates matrilysin activity in vivo, and this inhibition interferes with matrilysin-dependent airway epithelial repair.
In Specific Aim 1, 1 will determine the cellular contribution of TIMP-1 in the development of airway obliteration in the heterotopic tracheal transplant model.
In Specific Aim 2, I will investigate the mechanisms by which TIMP-1 limits matrilysin-mediated airway epithelial repair using in vitro and ex vivo culture systems.
In Specific Aim 3, 1 will demonstrate that TIMP-1 binds to matrilysin and disrupts matrilysin activity in vivo to inhibit airway epithelial repair. These studies will provide insight into the basic mechanisms by which TIMP-1 regulates airway epithelial repair with potential therapeutic implications in diseases such as OB.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL084396-05
Application #
7790603
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Rothgeb, Ann E
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$129,060
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
Gill, Sean E; Nadler, Samuel T; Li, Qinglang et al. (2016) Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation. Am J Respir Cell Mol Biol 55:243-51
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:
Chen, Peter; Edelman, Jeffrey D; Gharib, Sina A (2013) Comparative evaluation of miRNA expression between in vitro and in vivo airway epithelium demonstrates widespread differences. Am J Pathol 183:1405-1410
Gharib, Sina A; Altemeier, William A; Van Winkle, Laura S et al. (2013) Matrix metalloproteinase-7 coordinates airway epithelial injury response and differentiation of ciliated cells. Am J Respir Cell Mol Biol 48:390-6
Moon, Andres; Gil, Sucheol; Gill, Sean E et al. (2012) Doxycycline impairs neutrophil migration to the airspaces of the lung in mice exposed to intratracheal lipopolysaccharide. J Inflamm (Lond) 9:31
Altemeier, William A; Schlesinger, Saundra Y; Buell, Catherine A et al. (2012) Transmembrane and extracellular domains of syndecan-1 have distinct functions in regulating lung epithelial migration and adhesion. J Biol Chem 287:34927-35
Klaff, Lindy S; Gill, Sean E; Wisse, Brent E et al. (2012) Lipopolysaccharide-induced lung injury is independent of serum vitamin D concentration. PLoS One 7:e49076
Altemeier, William A; Schlesinger, Saundra Y; Buell, Catherine A et al. (2012) Syndecan-1 controls cell migration by activating Rap1 to regulate focal adhesion disassembly. J Cell Sci 125:5188-95
Lozon, Tricia I; Eastman, Alison J; Matute-Bello, Gustavo et al. (2011) PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 300:L422-9

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