The discovery and increased understanding of the function of antimicrobial peptides (AMPs) has revolutionized classical concepts of immune defense. AMPs act to protect against infections by direct antimicrobial action on microbes and by altering the host inflammatory response. The production of AMPs must be carefully regulated since disease can occur from either too little expression or abnormally high AMP production. In this application we wish to understand how expression of cathelicidin and other antimicrobial peptides are controlled, an important question for human health in light of prior studies showing abnormal production contributes to the pathophysiology of skin diseases such as atopic dermatitis, rosacea and psoriasis.
The specific aims of this application are as follows:
Specific Aim 1 : Define the mechanism and role of PTH/PTHrP in control of cathelicidin expression and skin infections.
Specific Aim 2 : Understand the impact of hypoxia and role of HIF in the cathelicidin response.
Specific Aim 3 : Define the cell-specific roles of cathelicidin in immune defense.
These aims will be accomplished by a combined approach of synergistic PIs, pairing mammalian immunology, genetic and biochemistry platforms with endocrinology and microbial genetics and infectious disease models. Preliminary data described in this application strongly support the novel and unexpected hypothesis that underlie Aims 1 and 2, and Aim 3 will be accomplished by the first use of the Cre-loxP system to target cathelicidin in mice. This system will provide a new tool through with the role of cell- specific cathelicidin can be understood. By learning how to control cathelicidin expression we will provide a new diagnostic and therapeutic tool and better understand the complex interactions between innate host immunity and our microbial environment.

Public Health Relevance

The actions of antimicrobial peptides are critical to normal immune function. We have discovered that these peptides are regulated by a complex series of cell specific events, and will control the ability of the skin to fight infection and control inflammation. This application will study how these are controlled and how cell specific expression influences skin infections and inflammatory skin diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052453-12
Application #
8637901
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Nasseri, M Faraz
Project Start
2002-09-15
Project End
2017-11-30
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
12
Fiscal Year
2014
Total Cost
$387,500
Indirect Cost
$137,500
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Borkowski, Andrew W; Kuo, I-Hsin; Bernard, Jamie J et al. (2015) Toll-like receptor 3 activation is required for normal skin barrier repair following UV damage. J Invest Dermatol 135:569-78
Nakagawa, Yukinobu; Gallo, Richard L (2015) Endogenous intracellular cathelicidin enhances TLR9 activation in dendritic cells and macrophages. J Immunol 194:1274-84
MacLeod, Daniel T; Nakatsuji, Teruaki; Wang, Zhenping et al. (2015) Vaccinia virus binds to the scavenger receptor MARCO on the surface of keratinocytes. J Invest Dermatol 135:142-50
Borkowski, Andrew W; Gallo, Richard L (2014) UVB radiation illuminates the role of TLR3 in the epidermis. J Invest Dermatol 134:2315-20
Franks, Sarah E; Ebrahimi, Celia; Hollands, Andrew et al. (2014) Novel role for the yceGH tellurite resistance genes in the pathogenesis of Bacillus anthracis. Infect Immun 82:1132-40
Sakoulas, George; Rose, Warren; Nonejuie, Poochit et al. (2014) Ceftaroline restores daptomycin activity against daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother 58:1494-500
Hata, T R; Audish, D; Kotol, P et al. (2014) A randomized controlled double-blind investigation of the effects of vitamin D dietary supplementation in subjects with atopic dermatitis. J Eur Acad Dermatol Venereol 28:781-9
van Sorge, Nina M; Cole, Jason N; Kuipers, Kirsten et al. (2014) The classical lancefield antigen of group a Streptococcus is a virulence determinant with implications for vaccine design. Cell Host Microbe 15:729-40
Sakoulas, George; Okumura, Cheryl Y; Thienphrapa, Wdee et al. (2014) Nafcillin enhances innate immune-mediated killing of methicillin-resistant Staphylococcus aureus. J Mol Med (Berl) 92:139-49
Neumann, Ariane; Berends, Evelien T M; Nerlich, Andreas et al. (2014) The antimicrobial peptide LL-37 facilitates the formation of neutrophil extracellular traps. Biochem J 464:3-11

Showing the most recent 10 out of 90 publications