In inflamed ainvay, changes in epithelial architecture, matrix, glands, and vessels promote obstruction and hypersecretion in chronic bronchitis and asthma. This project tests the hypothesis that peptidases control resolution of remodeling and other aspects of chronic ainway inflammafion. It uses novel approaches such as targeting peptidases in living cells with acfivity-based probes, probing immune cell interactions with real time imaging in mouse models of chronic infection, and exploring contribufions of genetic variation in mast cell peptidases to human asthma.
Aim 1 is to determine roles of the ainway epithelial peptidase prostasin in chronic infection. Epithelial integrity and hydrafion is essenfial for defense against microbes and toxins. Failure of barrier funcfion leads to chronic infection and remodeling, as in cystic fibrosis.
Aim 1 studies test the hypothesis that prostasin support of ainway ion flux and integrity is controlled by membrane anchoring, acfivafion, inhibition and shedding.
Aim 2 is to determine roles of mast cell peptidases in resolving inflammafion. Mast cell products can Inflict harm, but mouse studies suggest they also promote survival from septic peritonitis and pneumonia. By helping to resolve infection, their overall effect can be anti-inflammatory.
Aim 2 studies test the hypothesis that mast cell pepfidases promote resolufion of chronic inflammation.
Aim 3 is to determine impact of mast cell tryptase deficiency on chronic ainway inflammation. Tryptases are implicated in airway remodeling in allergic and autoimmune inflammation and in defense against bacterial infection and thus have the potential to produce as well as to resolve inflammation. Our recent work reveals that dysfunctional human tryptases are common and that Individuals and populafions vary strikingly in number of active tryptase genes inherited. By exploring connecfions between genotype and asthma, a disease associated not only with chronic inflammafion but with exacerbation by infection, the proposed studies test the hypothesis that differences in tryptase genotype contribute to inherited variafion in asthma severity and suscepfibility. Overall, the proposed studies are expected to identify mechanisms that suggest previously unexplored strategies to prevent or reverse the pathology of chronic airway inflammation.

Public Health Relevance

The proposed studies focus on identifying mechanisms of remodeling that may suggest previously unexplored strategies to prevent or reverse anatomical changes accompanying chronic ain/vay inflammafion. These studies are relevant to remodeiing-associated lung and airway diseases, including asthma, chronic bronchitis, and cysfic fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL024136-35
Application #
8646943
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
35
Fiscal Year
2014
Total Cost
$321,845
Indirect Cost
$112,756
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Caughey, George H (2016) Mast cell proteases as pharmacological targets. Eur J Pharmacol 778:44-55
Korhonen, Emilia A; Lampinen, Anita; Giri, Hemant et al. (2016) Tie1 controls angiopoietin function in vascular remodeling and inflammation. J Clin Invest 126:3495-510
Kim, Minah; Allen, Breanna; Korhonen, Emilia A et al. (2016) Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation. J Clin Invest 126:3511-25
Huang, Jennifer L; Woolf, Adrian S; Kolatsi-Joannou, Maria et al. (2016) Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases. J Am Soc Nephrol 27:69-77
Sen, Debasish; Jones, Stephen M; Oswald, Erin M et al. (2016) Tracking the Spatial and Functional Gradient of Monocyte-To-Macrophage Differentiation in Inflamed Lung. PLoS One 11:e0165064
Greenland, John R; Wong, Charissa M; Ahuja, Rahul et al. (2016) Donor-Reactive Regulatory T Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts. Transplantation 100:2090-8
Headley, Mark B; Bins, Adriaan; Nip, Alyssa et al. (2016) Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531:513-7
Lindsay, Robin S; Corbin, Kaitlin; Mahne, Ashley et al. (2015) Antigen recognition in the islets changes with progression of autoimmune islet infiltration. J Immunol 194:522-30
Le, Catherine T K; Laidlaw, Grace; Morehouse, Christopher A et al. (2015) Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation. Am J Pathol 185:2949-68
Bose, Oishee; Baluk, Peter; Looney, Mark R et al. (2015) Mast cells present protrusions into blood vessels upon tracheal allergen challenge in mice. PLoS One 10:e0118513

Showing the most recent 10 out of 584 publications