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Effect Of Ultraviolet Radiation On Development Of Effector And Memory T Cells To Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$498,328.00
Summary
Australia has the highest incidence of skin cancer in the world, due to our lifestyle that involves high levels of exposure to sunlight. Skin cancer, including melanoma can be destroyed by the immune system, but sunlight inhibits immunity, enabling skin tumours to grow. Our aim is to determine how sunlight affects the activation of effector anti-melanoma T cells, and their development into memory T cells, and the dose of sunlight required to have this effect. It is unknown whether ultraviolet ra ....Australia has the highest incidence of skin cancer in the world, due to our lifestyle that involves high levels of exposure to sunlight. Skin cancer, including melanoma can be destroyed by the immune system, but sunlight inhibits immunity, enabling skin tumours to grow. Our aim is to determine how sunlight affects the activation of effector anti-melanoma T cells, and their development into memory T cells, and the dose of sunlight required to have this effect. It is unknown whether ultraviolet radiation in sunlight suppresses the activation of effector cells that mediate rejection of skin tumours, or their development into memory cells, or migration of activated-memory lymphocytes into skin tumours. The number of antigen reactive T cells is a key issue for tumour immunity and the aim of many clinical immunotherapy trials is to boost these to levels that can effectively destroy the tumour. It is important to establish whether low doses of sunlight readily achievable during normal living, or only higher exposures received when sunbaking, inhibit the number of these effector T cells, and their migration into skin tumours. It is important to determine whether there is a relatively safe threshold level of sunlight exposure to be able to give better advice on sunlight doses that can be achieved without causing serious deleterious health effects. Also these levels of sunlight may interfere with immunotherapy trials and therefore need to be determined. An additional outcome will be to determine whether chemopreventative agents that enhance recovery from sunlight induced suppression of skin allergies are also protective for anti-tumour immunity. The establishment of procedures for prevention of suppression of anti-tumour immunity may enhance the number of T cells activated by natural immunity or during immunotherapy, thereby improving immune rejection of melanoma.Read moreRead less
Quantitiative Assessment Of Solar UV Exposure For Vitamin D Synthesis In Australian Adults
Funder
National Health and Medical Research Council
Funding Amount
$1,162,536.00
Summary
This research program will add significantly to our current scientific understanding of the dual health outcomes of UV exposure (Vitamin D and skin cancer) . This project is in line with Australia's R and D Priorities, in that it will result in direct and indirect social and economic benefits to Australia by applying the scientific knowledge gained through this research to develop public health initiatives to improve some of Australia's most significant and costly health problems.
There is a need for a greater understanding of the complex relationship between sun exposure and the production of Vitamin D. This study will expand on the recently-completed AusD study to examine how personal, behavioural, and environmental factors impact on intra-individual seasonality in Vitamin D production. The study findings will guide the development of specific, evidence-based public health recommendation that balance the risks and benefits of sun exposure.
Squamous cell carcinoma of the skin is extremely common in Australia, resulting in disfiguring surgeries and deaths. Although cumulative sun exposure is important, some people are very susceptible, and we do not know why. This project hinges on the notion that skin cancer is a complex (many genes involved). We will utilize novel systems to harness this complexity to understand why some people are resistant and others very susceptible so as to design appropriate control measures and treatments.
DNA Damage Induced By UVA And UVB In Squamous Cell Carcinoma Progression
Funder
National Health and Medical Research Council
Funding Amount
$65,000.00
Summary
Australia has the highest incidence of skin cancer in the world. This results from immigration of individuals with fair skin to Australia. Skin cancer is three times as common as all other cancers combined. Overall, the incidence of skin cancer continues to rise in Australia and it will be several years before the true effectiveness of preventative programs are known. In the meantime, 1000 Australians die each year from skin cancer. Modern sunscreens, even those with high SPF and labelled as bro ....Australia has the highest incidence of skin cancer in the world. This results from immigration of individuals with fair skin to Australia. Skin cancer is three times as common as all other cancers combined. Overall, the incidence of skin cancer continues to rise in Australia and it will be several years before the true effectiveness of preventative programs are known. In the meantime, 1000 Australians die each year from skin cancer. Modern sunscreens, even those with high SPF and labelled as broad spectrum do not protect very well from UVA, though they are very effective UVB filters. Most sunscreens absorb or reflect only about 50% as much UVA as UVB. Thus sunscreen use alters the spectrum of UV received. This is an important issue, because if sunscreens are used to prolong sun exposure they will selectively increase the amount of UVA reaching the skin, and the sun contains a lot more UVA than UVB. There is only limited evidence to suggest they protect from skin cancer in humans whereas there is good evidence that they protect from precursor lesions. We have developed a new hypothesis, that UVB is primarily responsible for development of preneoplastic lesions (solar keratosis and dysplastic nevi) whereas UVA plays a relatively more important role in their progression to malignancy. This hypothesis would explain why sunscreens are more effective at preventing nevi and solar keratosis formation than they are at preventing melanoma and squamous cell carcinoma. Until the action spectrum defining the wavelengths responsible for skin cancer induction is known, the optimal methods for protection from skin cancer will be difficult if not impossible to design. That different wavelengths may be involved in different phases of skin cancer development in humans is a novel hypothesis: if it is correct it will have profound implications for both the design of sunscreens and our current public health programmes for skin cancer prevention.Read moreRead less
Tracking Epidermal Clonal Evolution During Skin Cancer Induction And Progression
Funder
National Health and Medical Research Council
Funding Amount
$558,168.00
Summary
Skin cancer is the most frequent form of cancer in Australia and in many parts of the world. It is strongly connected to ultraviolet radiation from the sun. In this project, we will use our capacity to track individual cells, to observe the heterogeneity of tumours and the lesions that precede them. We will show the importance of this heterogeneity in tumour progression unveiling the limits of current therapies against skin cancer.
The Melanoma Susceptibility Gene Product P16 Functions In A UV-induced Cell Cycle Checkpoint In Human Skin
Funder
National Health and Medical Research Council
Funding Amount
$204,131.00
Summary
The contribution of the ultraviolet component of sunlight to skin cancer generally, and melanoma in particular, is widely acknowledged. However, the actual mechanism by which ultraviolet radiation changes the normal skin melanocytes, the pigmented skin cells, into cancerous melanomas is unclear. Several years ago, a gene was identified that was found to be mutated in a high proportion of sporadic melanomas, and was also found to be mutated in a proportion of families with a predisposition to dev ....The contribution of the ultraviolet component of sunlight to skin cancer generally, and melanoma in particular, is widely acknowledged. However, the actual mechanism by which ultraviolet radiation changes the normal skin melanocytes, the pigmented skin cells, into cancerous melanomas is unclear. Several years ago, a gene was identified that was found to be mutated in a high proportion of sporadic melanomas, and was also found to be mutated in a proportion of families with a predisposition to developing melanoma. This melanoma susceptibility gene, p16, can act to block cells growth, thus loss of this gene function in disease could lead to uncontrolled cell growth, a hallmark of cancer. This proposal investiagtes the role of p16 in responses of normal skin cells to ultraviolet radiation. We will examine the increased levels of p16 detected in skin after exposure to low doses of ultraviolet radiation and attempt to define the growth responses of these cells to the increased p16 levels. This project will help to establish the normal role of p16 in cellular responses to ultraviolet radiation, and may also identify novel targets for diagnosis, prevention or treatment of melanoma.Read moreRead less
The Role Of Past Sun Exposure, Infection History And Other Exogenous Factors In Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$92,011.00
Summary
Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the brain and spinal cord that leads to various degrees of disability. The causes of MS are not yet known, and there is presently no cure. However, there is strong evidence that both an inherited susceptibility and environmental factors are important. This environmental case control study will be conducted in Tasmania and will run concurrent to a genetic project on MS which allows assessment of gene-environment interactions. ....Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease of the brain and spinal cord that leads to various degrees of disability. The causes of MS are not yet known, and there is presently no cure. However, there is strong evidence that both an inherited susceptibility and environmental factors are important. This environmental case control study will be conducted in Tasmania and will run concurrent to a genetic project on MS which allows assessment of gene-environment interactions. It focuses on infections, timing of childhood infections and long term sun exposure. It has been suggested that MS may be due to an immune disturbance following viral infection and that the timing of childhood infections may be initially important. Also, in Australia, there is a sevenfold increase in MS prevalence as one moves from Queensland to Tasmania. This latitudinal gradient might be due to ultra violet radiation, through an influence on immune function. Beside those main focuses, the study will include other environmental factors like chemicals, diet and vaccinations. Hopefully this project will contribute to a better understanding of the causes of MS, which are relevant for preventative strategies and devising optimal treatment.Read moreRead less
Susceptibility Of The Basal Layer Of Human Epidermis To UVA Oxidative Damage Due To Pheomelanin And Suboptimal DNA Repair
Funder
National Health and Medical Research Council
Funding Amount
$559,354.00
Summary
Australia has the highest incidence of skin cancer in the world. It is important to understand how sunlight causes skin cancer and the wavelengths involved in order to devise effective preventative and therapeutic strategies. Our proposal is that the cells in the skin that give rise to the most common forms of skin cancer, squamous cell carcinoma and basal cell carcinoma, are particularly vulnerable to UVA. We aim to study why this is the case and whether this vulnerability can be prevented.
A Single-stranded DNA Binding Protein Implicated In The Cellular Response To DNA Damage.
Funder
National Health and Medical Research Council
Funding Amount
$503,816.00
Summary
Humans have evolved multiple mechanisms to ensure the integrity of their genetic information, which is carried by DNA. Each cell suffers more than 100 000 insults a day to its DNA; therefore an effective DNA damage response is crucial for the maintenance of genetic integrity and for survival. This research proposal aims to explore the molecular actions of hSSB2, a newly discovered player in the cell's arsenal for repairing harmful DNA damage.