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.
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.
|Greenland, J R; Jewell, N P; Gottschall, M et al. (2014) Bronchoalveolar lavage cell immunophenotyping facilitates diagnosis of lung allograft rejection. Am J Transplant 14:831-40|
|Baluk, Peter; Adams, Alicia; Phillips, Keeley et al. (2014) Preferential lymphatic growth in bronchus-associated lymphoid tissue in sustained lung inflammation. Am J Pathol 184:1577-92|
|Sutherland, Rachel E; Barry, Sophia S; Olsen, Joanna S et al. (2014) Dipeptidyl peptidase I controls survival from Klebsiella pneumoniae lung infection by processing surfactant protein D. Biochem Biophys Res Commun 450:818-23|
|Gérard, Audrey; Patino-Lopez, Genaro; Beemiller, Peter et al. (2014) Detection of rare antigen-presenting cells through T cell-intrinsic meandering motility, mediated by Myo1g. Cell 158:492-505|
|Ortiz-Muñoz, Guadalupe; Mallavia, Beñat; Bins, Adriaan et al. (2014) Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood 124:2625-34|
|Giannotta, Monica; Benedetti, Sara; Tedesco, Francesco Saverio et al. (2014) Targeting endothelial junctional adhesion molecule-A/ EPAC/ Rap-1 axis as a novel strategy to increase stem cell engraftment in dystrophic muscles. EMBO Mol Med 6:239-58|
|Broz, Miranda L; Binnewies, Mikhail; Boldajipour, Bijan et al. (2014) Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26:638-52|
|Patnode, Michael L; Bando, Jennifer K; Krummel, Matthew F et al. (2014) Leukotriene B4 amplifies eosinophil accumulation in response to nematodes. J Exp Med 211:1281-8|
|Baluk, Peter; Phillips, Keeley; Yao, Li-Chin et al. (2014) Neutrophil dependence of vascular remodeling after Mycoplasma infection of mouse airways. Am J Pathol 184:1877-89|
|Lelkes, Efrat; Headley, Mark B; Thornton, Emily E et al. (2014) The spatiotemporal cellular dynamics of lung immunity. Trends Immunol 35:379-86|
Showing the most recent 10 out of 544 publications