Objective
Solar ultraviolet radiation (UVR) causes skin cancer with serious health and economic consequences. The interaction of skin cancer risk factors is complex and poorly understood but genotypic, phenotypic, adaptive and environmental aspects are important. These vary in different European populations. Our aim is to study the genetic and pathophysiological basis of skin cancer risk factors, to examine their interaction and to determine their relevance to individual risk. We propose a combined epidemiological, photobiological and molecular approach to examine UVR exposure, skin type, anti-oxidant status, sunburn cell (SBC) formatior (apoptosis), UVR-induced immunosuppression and the generation of reactive oxygen species (ROS).
UVR exposure data Personal UVR exposure profiles, determined with miniature electronic dosimeters, wil be undertaken in two different European populations. These data will be used to model cumulative individual UVR exposure dose by correlation with quantitative measurements of cumulative sunlight-induced biological changes such as skin photoageing. Calculated cumulative exposure dose will be used, in association with other biological and physical risk factors, such as skin type, anti-oxidant status and number of sunburning episodes, to determine individual skin cancer risk. The personal UVR measurements can also be used to validate recall of episodes of sunburning which is widely used in epidemiological studies.
Acute and chronic effects of UVR on human skin Studies on healthy volunteers of different skin types, associated with different risks of skin cancer, and on skin cancer patients will be performed.
- We will determine detailed UVB action spectra in human skin in vivo for SBC, p53 gene expression and cytokine release, parameters which we believe represent risk factors in the immunosuppressive, inflaMmatory and DNA mediated mechanisms leading to skin cancer.
- We will identify the relationship between UVR dose, SBC formation and risk of skin cancer.
- Adaptive/photoprotective responses from chronic UVR exposure will be assessed using SBC formation, p53 upregulation and cytokine induction as relevant biological endpoints.
Sunburn cellformation We hypothesise that defective UVR-induced apoptosis (programmed cell death) in skin is a risk factor in human skin cancer. We will study some of the molecular control mechanisms of UVR-induced apoptosis in skin cells in vitro and determine if they are relevant in vivo by studies on humans and transgenic mice. These studies may lead to an in vitro skin cancer risk screening test.
UVR-induced immunosuppression The prevalence of the 'UVR-susceptible' trait will be determined and its relevance to skin cancer examined in combination with genetic anti-oxidant deficiency.
Generation of reactive oxygen species The role of UVR generated ROS will be studied in vivo and in vitro.
The antioxidant status of volunteers and skin cancer patients will be related to sunburn cell formation.
Mass spectrometric methods will be developed to identify oxidation products of specific phospholipids associated with apoptosis and membrane function.
Direct UVB effects on dermal microvasculature and inflammation Sunburn (inflammation) is a risk factor for malignant melanoma. We have shown that UVB penetration of human epidermis in vivo is greater than predicted by in vitro models. We will now measure UVB penetration of human dermis in vivo using DNA photodamage as end point. Activation of the dermal microvasculature is critical for inflammation. In vitro studies will define the direct effects of UVR on endothelial cell cytokine receptor expression and function, chemokine release, and adhesion molecule expression.
This multidisciplinary approach requires a wide range of facilities, clinical and scientific expertise that cannot be provided by a single laboratory. The in vivo studies are dependent on healthy volunteers with different skin types and skin cancer patients. Photobiological protocols and dosimetry will be standardised by the project co-ordinator.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- natural sciences chemical sciences electrochemistry electrolysis
- medical and health sciences clinical medicine oncology skin cancer melanoma
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Coordinator
SE1 7EH London
United Kingdom
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