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
Kumaraswamy, Monika; Do, Carter; Sakoulas, George et al. (2018) Listeria monocytogenes endocarditis: case report, review of the literature, and laboratory evaluation of potential novel antibiotic synergies. Int J Antimicrob Agents 51:468-478
Dokoshi, Tatsuya; Zhang, Ling-Juan; Nakatsuji, Teruaki et al. (2018) Hyaluronidase inhibits reactive adipogenesis and inflammation of colon and skin. JCI Insight 3:
Sato, Emi; Williams, Michael R; Sanford, James A et al. (2017) The parathyroid hormone family member TIP39 interacts with sarco/endoplasmic reticulum Ca2+ - ATPase activity by influencing calcium homoeostasis. Exp Dermatol 26:792-797
Lee, Ernest Y; Takahashi, Toshiya; Curk, Tine et al. (2017) Crystallinity of Double-Stranded RNA-Antimicrobial Peptide Complexes Modulates Toll-Like Receptor 3-Mediated Inflammation. ACS Nano 11:12145-12155
Sakoulas, George; Rose, Warren; Berti, Andrew et al. (2017) Classical ?-Lactamase Inhibitors Potentiate the Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus and Colistin against Acinetobacter baumannii. Antimicrob Agents Chemother 61:
Williams, Michael R; Nakatsuji, Teruaki; Sanford, James A et al. (2017) Staphylococcus aureus Induces Increased Serine Protease Activity in Keratinocytes. J Invest Dermatol 137:377-384
Kulkarni, Nikhil N; Adase, Christopher A; Zhang, Ling-Juan et al. (2017) IL-1 Receptor-Knockout Mice Develop Epidermal Cysts and Show an Altered Innate Immune Response after Exposure to UVB Radiation. J Invest Dermatol 137:2417-2426
Valderrama, J Andrés; Riestra, Angelica M; Gao, Nina J et al. (2017) Group A streptococcal M protein activates the NLRP3 inflammasome. Nat Microbiol 2:1425-1434
Munguia, Jason; LaRock, Doris L; Tsunemoto, Hannah et al. (2017) The Mla pathway is critical for Pseudomonas aeruginosa resistance to outer membrane permeabilization and host innate immune clearance. J Mol Med (Berl) 95:1127-1136
Nakatsuji, Teruaki; Chen, Tiffany H; Narala, Saisindhu et al. (2017) Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med 9:

Showing the most recent 10 out of 157 publications