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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Nasseri, M Faraz
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Williams, Michael R; Nakatsuji, Teruaki; Sanford, James A et al. (2016) Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes. J Invest Dermatol :
Nakatsuji, Teruaki; Chen, Tiffany H; Two, Aimee M et al. (2016) Staphylococcus aureus Exploits Epidermal Barrier Defects in Atopic Dermatitis to Trigger Cytokine Expression. J Invest Dermatol 136:2192-2200
Adase, Christopher A; Borkowski, Andrew W; Zhang, Ling-Juan et al. (2016) Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells. J Biol Chem 291:11635-46
Cole, Jason N; Nizet, Victor (2016) Bacterial Evasion of Host Antimicrobial Peptide Defenses. Microbiol Spectr 4:
Zhang, Ling-Juan; Sen, George L; Ward, Nicole L et al. (2016) Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-β Production by Epidermal Keratinocytes during Skin Injury. Immunity 45:119-30
Sato, Emi; Muto, Jun; Zhang, Ling-Juan et al. (2016) The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation. J Invest Dermatol 136:1449-59
Kumaraswamy, Monika; Lin, Leo; Olson, Joshua et al. (2016) Standard susceptibility testing overlooks potent azithromycin activity and cationic peptide synergy against MDR Stenotrophomonas maltophilia. J Antimicrob Chemother 71:1264-9
Zhang, Ling-juan; Guerrero-Juarez, Christian F; Hata, Tissa et al. (2015) Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347:67-71
LaRock, Christopher N; Döhrmann, Simon; Todd, Jordan et al. (2015) Group A Streptococcal M1 Protein Sequesters Cathelicidin to Evade Innate Immune Killing. Cell Host Microbe 18:471-7
Pence, Morgan A; Haste, Nina M; Meharena, Hiruy S et al. (2015) Beta-Lactamase Repressor BlaI Modulates Staphylococcus aureus Cathelicidin Antimicrobial Peptide Resistance and Virulence. PLoS One 10:e0136605

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