Mast Cells Determine Susceptibility To Induction Of Systemic Immunomodulation By UVB Radiation
Funder
National Health and Medical Research Council
Funding Amount
$194,993.00
Summary
The ultraviolet B component of sunlight causes an immunosuppression in humans such that UV-induced tumours develop. In a murine model, we have shown that dermal mast cells at the irradiated site are crucially important in the mechanisms by which UVB stimulates this immunosuppression. In this project we wish to study in more depth the mechanisms by which sunlight stimulates mast cells to produce molecules which in turn signal immunosuppressive events. We hypothesise that there is an intermediary ....The ultraviolet B component of sunlight causes an immunosuppression in humans such that UV-induced tumours develop. In a murine model, we have shown that dermal mast cells at the irradiated site are crucially important in the mechanisms by which UVB stimulates this immunosuppression. In this project we wish to study in more depth the mechanisms by which sunlight stimulates mast cells to produce molecules which in turn signal immunosuppressive events. We hypothesise that there is an intermediary by which sunlight stimulates mast cell activity; we hypothesise that cis-urocanic acid may be involved directly or indirectly in this process. There is considerable evidence that histamine may be the major product of mast cells involved in this process; however it is unknown whether its primary action is on keratinocytes (stimulating prostanoid production), antigen presenting cells or lymph node cells. This project will also investigate the relationship of studies with mice to UVB-induced systemic immunosuppression in humans. Non-sun-exposed skin from controls and patients with non-melanoma skin cancers will be examined and dermal mast cell prevalence evaluated; we hypothesise that people with high dermal mast cell numbers are more prone to immunosuppression and thus, the outgrowth of UV-induced non-melanoma skin cancers. We hypothesise that there may also be qualitative differences in the mast cells of UV-sensitive and UV-resistant individuals; variations may occur in the granule contents of neutral proteinases or cytokines. It is necessary that we better understand the basis of immune system modulation by UVB that allows non-melanoma skin cancer development as these patients have a 20-30% higher risk of death from other cancers.Read moreRead less
Molecular Basis For The Emergence Of Community Acquired Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$427,518.00
Summary
Golden Staph is a major problem in our hospitals but serious Golden Staph infections are increasingly common in the community, among otherwise healthy people who have had no contact with hospitals. This project will find out how Golden Staph is evolving to become more likely to cause disease in the community. This knowledge can then be used to design new strategies for early detection, prevention and treatment.
Targeted Redox Therapy For Photoageing Prevention And Treatment
Funder
National Health and Medical Research Council
Funding Amount
$562,815.00
Summary
Our goal is to target natural reduction/oxidation (redox) modifiers, i.e. niacin and sulforaphane, to the skin deeper layers to treat photoageing. Both drugs have been separately shown to prevent UV induced skin cancer. The outcomes of this project will be safer and more effective prevention and treatment of sun damaged skin. This project can provide health benefits to Australians from improved treatment of sun damage, and economic benefits to the nation.
Infectious And Lifestyle Determinants Of Non-melanoma Skin Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$983,711.00
Summary
Basal and squamous cell skin cancers are the leading cancers in Australia, with about 2% of the population developing them each year. As well as sun exposure, a number of other factors have been thought to effect these cancers. This study will examine if factors such as smoking, alcohol consumption and infection with certain skin related human papillomaviruses also increase their risk. Even a small effect may make a big difference when it comes to preventing these common cancers.
Effects Of Nevogenesis Susceptibility Genes And Phenotypic Correlation With Dermoscopic Characteristics Of Nevi
Funder
National Health and Medical Research Council
Funding Amount
$554,099.00
Summary
Melanoma is a form of skin cancer that arises from the cells that produce pigment and is a major public health issue in Australia. We will examine the relationship between the form, structure and colour of existing types of moles and their subsequent risk of developing into melanoma. This will be the first study to combine dermoscopy, a non-invasive examination technique, with DNA tests of the genes that determine skin, hair and eye colour, aiding in the early prediction and diagnosis of skin ca ....Melanoma is a form of skin cancer that arises from the cells that produce pigment and is a major public health issue in Australia. We will examine the relationship between the form, structure and colour of existing types of moles and their subsequent risk of developing into melanoma. This will be the first study to combine dermoscopy, a non-invasive examination technique, with DNA tests of the genes that determine skin, hair and eye colour, aiding in the early prediction and diagnosis of skin cancer.Read moreRead less
Determination Of An Action Spectrum For Ultraviolet Radiation-induced Immunosuppression In Humans
Funder
National Health and Medical Research Council
Funding Amount
$213,500.00
Summary
Ultraviolet (UV) radiation causes mutations in the skin which can develop into cancers many years later. The skin's immune system is an important defence that prevents most potentially cancerous cells from developing into skin tumours. UV also suppresses skin immunity, allowing cancer cells to proliferate unchecked. There is also evidence that this UV-induced immunosuppression may have important effects on infectious diseases such as herpes virus, leprosy and tropical ulcers. Sunlight contains U ....Ultraviolet (UV) radiation causes mutations in the skin which can develop into cancers many years later. The skin's immune system is an important defence that prevents most potentially cancerous cells from developing into skin tumours. UV also suppresses skin immunity, allowing cancer cells to proliferate unchecked. There is also evidence that this UV-induced immunosuppression may have important effects on infectious diseases such as herpes virus, leprosy and tropical ulcers. Sunlight contains UVB, which causes sunburn, and UVA. Until recently, UVA was thought to have little effect on skin immunity. We have previously shown that both broadband UVB and UVA are immunosuppressive, even after single exposures equivalent to 8 minutes of sunlight. It is not known which UVA wavelengths are most immunosuppressive. These studies will use a xenon arc solar simulator and a series of interference filters to produce narrow UVB and UVA wavebands. The effects of these wavebands on humans can be studied by deliberately eliciting immune responses to substances which volunteers are already sensitive to. One model of skin immunity in these studies is allergy to nickel (in earrings and costume jewellery), which affects 10% of women. The volunteers' backs are exposed to different UV wavelengths, and then nickel patches are taped to both the UV-exposed areas and adjacent, unexposed areas. By comparing the intensity (redness and thickness) of these nickel reactions, immunosuppression caused by each waveband can be measured. Similarly, the Mantoux reaction (in people vaccinated against tuberculosis) provides another, complementary model of skin immunity. Knowledge of the immune effects of different UV wavelengths (an action spectrum for UV immunosuppression) would improve understanding of skin cancer and enable development of better sunscreens, which currently offer only partial immune protection.Read moreRead less
The discoveries made to date and the proposed studies point to an intrinsic role for vitamin D compounds in skin in providing protection from sun damage. As a result of sun exposure, increased concentrations of vitamin D compounds in skin will be generated and this is likely to provide protection against further UV damage, in much the same way as increased pigmentation and increased thickness of the outer layer of skin. Furthermore, the studies are designed to test whether vitamin D compounds wh ....The discoveries made to date and the proposed studies point to an intrinsic role for vitamin D compounds in skin in providing protection from sun damage. As a result of sun exposure, increased concentrations of vitamin D compounds in skin will be generated and this is likely to provide protection against further UV damage, in much the same way as increased pigmentation and increased thickness of the outer layer of skin. Furthermore, the studies are designed to test whether vitamin D compounds which have minimal effects on serum calcium, could nevertheless be used topically in association with a sunscreen or moisturizer to add to sun protection. As Australia has the highest skin cancer rates in the world, this would be of significant health and economic value.Read moreRead less
Molecular Determinants Of Subcellular Localisation And Function Of The Transmembrane 4 Superfamily Protein, PETA-3
Funder
National Health and Medical Research Council
Funding Amount
$322,911.00
Summary
Several years ago we identified the cell membrane protein PETA-3-CD151 based on its ability to cause activation of blood platelets, suggesting a role in thrombosis. More recently we found that the protein is present in a variety of tissues, although its distribution in those tissues is often restricted. It is abundant in a variety of cancer cells, and is present on tissue mast cells that mediate allergic reactions. PETA-3-CD151 forms complexes with molecules (integrins) that are associated with ....Several years ago we identified the cell membrane protein PETA-3-CD151 based on its ability to cause activation of blood platelets, suggesting a role in thrombosis. More recently we found that the protein is present in a variety of tissues, although its distribution in those tissues is often restricted. It is abundant in a variety of cancer cells, and is present on tissue mast cells that mediate allergic reactions. PETA-3-CD151 forms complexes with molecules (integrins) that are associated with cell adhesion and migration, and antibodies to this protein inhibit cell movement. Thus PETA-3-CD151 appears to be involved in cellular interactions that are critical for normal tissue development and function, and may be involved in several disease processes including cancer invasion and metastasis. The molecular basis of PETA-3-CD151 function is not understood and is the focus of this application.Read moreRead less
The Role Of Keratin End-domains In Filament Biology
Funder
National Health and Medical Research Council
Funding Amount
$139,235.00
Summary
The skin is the largest organ in the body and is the main interface between the organism and the external environment. It protects us from UV radiation, microbial invasion and chemical attack. It is able to repair itself and in fact, is continually renewing itself. In this study, we propose to examine the biology of keratins and the filament networks they form. Keratins are the most abundant proteins present in the epidermis, the outer layer of the skin. Keratins form a cellular skeleton that re ....The skin is the largest organ in the body and is the main interface between the organism and the external environment. It protects us from UV radiation, microbial invasion and chemical attack. It is able to repair itself and in fact, is continually renewing itself. In this study, we propose to examine the biology of keratins and the filament networks they form. Keratins are the most abundant proteins present in the epidermis, the outer layer of the skin. Keratins form a cellular skeleton that reinforces skin cells to help them withstand mechanical trauma. Mutations in these proteins result in a much weaker skeleton and ultimately in disease. We will examine how the keratin building blocks are transported around the cell to where they are needed. We will also determine the effect of mutations in this transport process on the biology of the cell. These studies may provide important clues into certain inherited skin disorders.Read moreRead less