The signals and processes by which diverse stimuli lead to keratinocyte cytokine production and cytotoxicity are presently not well understood. Moreover, chronic stimulation by agents such as ultraviolet radiation leads to malignancy. Recent studies have demonstrated that ultraviolet B radiation (UVB) damages human keratinocytes (HK) in part by inducing oxidative stress and cytokine production. Severe UVB damage to the keratinocyte can also result in apoptosis, or programmed cell death. Previous studies by our group and others have indicated that keratinocyte damage, especially via agents that result in oxidative stress results in the production of glycerophosphocholines (GPC) that can act as agonists for the Platelet-activating Factor (PAF) or the peroxisome proliferator activated receptor gamma (PPAR?) systems. The long-term objective of this ongoing research proposal is to elucidate the role of these oxidized GPCs in the acute UVB-induced photoresponse.
Three specific aims are designed to test the hypothesis that UVB-mediated oxidative damage to the keratinocyte results in the production of novel ox-GPCs that activate the PAF-R and PPAR? systems. These novel lipids augment cytokine production, modulate apoptosis, and induce keratinocyte proliferation: 1). The effect of these ox-GPCs on acute UVB-mediated inflammation, cytokine production, DNA damage/apoptosis and proliferation will be assessed in mice deficient in PAF-R and epidermal PPAR?;2) Mass spectrometric methodologies will be used to structurally characterize ox-GPCs produced in response to UVB; and 3) The role of these ox-GPCs in the acute UVB photoresponse in humans will be determined. We anticipate that these studies using novel in vitro and in vivo model systems and novel methodologies will result in the characterization of ox-GPCs with PAF-R- and PPAR?- agonistic effects in acute UVB-induced keratinocyte cytokine production, cytotoxicity, and proliferation. This information will aid in the understanding of the mechanism(s) by which oxidative stress can be involved in cutaneous pathophysiology. Since these mediators would be produced in response to oxidative stress in other organ systems, these studies should provide important insights into and tools to study the impact of ox-GPCs in human pathophysiology.

Public Health Relevance

Ultraviolet B radiation (UVB) induces profound effects upon keratinocytes and is responsible for the majority of skin cancers. Recent studies by our group have demonstrated that UVB induces the production of glycerophosphocholines (GPC) that can act as agonists for the Platelet-activating Factor (PAF) or the peroxisome proliferator activated receptor gamma (PPAR?) systems. The proposed studies will determine the structures of, and define the role of these novel lipid mediators in the acute UVB photoresponse.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062996-14
Application #
8442893
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Sarkar, Rita
Project Start
1999-07-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2015-03-31
Support Year
14
Fiscal Year
2013
Total Cost
$362,855
Indirect Cost
$127,235
Name
Indiana University-Purdue University at Indianapolis
Department
Dermatology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Sahu, Ravi P; Ocana, Jesus A; Harrison, Kathleen A et al. (2014) Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor. Cancer Res 74:7069-78

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