Overview of Program Project: This is a resubmission of a renewal of a Program Project Grant (PPG) application to study the mucosal barrier in infection and inflammation. Ninety-five percent of infectious agents enter through exposed mucosal surfaces, such as the respiratory, gastrointestinal, mammary and urogenital tracts. Mucosal infections include bacterial and viral pneumonia, SARS, TB, AIDS and other sexually transmitted diseases, numerous opportunistic, emerging and re-emerging infections, and biological warfare/terrorist agents. Mucosal surfaces are lined by epithelial cells, usually in a monolayer. The epithelial cell layer is the principal barrier to entry of infectious agents, allergens and other noxious antigens. Fundamentally, the epithelial layer is the most basic component of the innate mucosal immune system. In this Program Project we focus on two broad and inter-related areas of how the epithelial layer performs its functions in mucosal immune protection, with a particular emphasis on pulmonary epithelium. Projects 1 (Mostov), 2 (Engel) and 3 (Rosen) study mechanisms of epithelial wound healing, the roles of sulfs (sulfatases which modify heparan sulfate proteoglycans) in epithelial response to injury and the interaction of polarized cells with a bacterial pathogen. Project 4 (Werb) is focused on how inflammatory cells cross the epithelial barrier to enter the lumen of the organ. Project 1 uses two novel three dimensional cell culture models of epithelial wound healing. Project 2 focuses on the opportunistic pathogen, Pseudomonas aeruginosa, as a model for epithelial pathogen interaction. Project 3 examines how sulfs participate in epithelial wound healing. Project 4 focuses on the role of proteases and sulfs in regulating inflammatory cell recruitment and migration in mucosal tissues. Core A supports the Program Project administratively. Core B (Matthay) provides primary human and rodent lung epithelial cells in monolayer cultures, three-dimensional models and lung slices, as well as functional studies in mice. Core C has an array of four microscopes suitable for three- and four-dimensional analysis of cell dynamics for in vitro studies as well as experiments in living, anesthetized mice. Most infectious agents enter the body through exposed mucosal surfaces. These surfaces are lined by epithelial cells, most commonly in a single layer. We are studying how this epithelial barrier protects us against infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-IPG-I (M1))
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Rothermel, Annette L
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University of California San Francisco
Anatomy/Cell Biology
Schools of Medicine
San Francisco
United States
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Datta, Anirban; Sandilands, Emma; Mostov, Keith E et al. (2017) Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition. Cell Signal 40:91-98
Singer, Mark S; Phillips, Joanna J; Lemjabbar-Alaoui, Hassan et al. (2015) SULF2, a heparan sulfate endosulfatase, is present in the blood of healthy individuals and increases in cirrhosis. Clin Chim Acta 440:72-8
Plaks, Vicki; Boldajipour, Bijan; Linnemann, Jelena R et al. (2015) Adaptive Immune Regulation of Mammary Postnatal Organogenesis. Dev Cell 34:493-504
Casbon, Amy-Jo; Reynaud, Damien; Park, Chanhyuk et al. (2015) Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci U S A 112:E566-75
Bucior, Iwona; Tran, Cindy; Engel, Joanne (2014) Assessing Pseudomonas virulence using host cells. Methods Mol Biol 1149:741-55
Tran, Cindy S; Eran, Yoni; Ruch, Travis R et al. (2014) Host cell polarity proteins participate in innate immunity to Pseudomonas aeruginosa infection. Cell Host Microbe 15:636-43
Bonnans, Caroline; Lohela, Marja; Werb, Zena (2014) Real-time imaging of myeloid cells dynamics in ApcMin/+ intestinal tumors by spinning disk confocal microscopy. J Vis Exp :51916
Kwon, Sang-Ho; Liu, Kathleen D; Mostov, Keith E (2014) Intercellular transfer of GPRC5B via exosomes drives HGF-mediated outward growth. Curr Biol 24:199-204
Kim, J H; Chan, C; Elwell, C et al. (2013) Endosulfatases SULF1 and SULF2 limit Chlamydia muridarum infection. Cell Microbiol 15:1560-71
Maltseva, Inna; Chan, Matilda; Kalus, Ina et al. (2013) The SULFs, extracellular sulfatases for heparan sulfate, promote the migration of corneal epithelial cells during wound repair. PLoS One 8:e69642

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