How Important Is Collagen Destruction In Arthritis? A Study With Collagenase-resistant Knockin Mice
Funder
National Health and Medical Research Council
Funding Amount
$529,723.00
Summary
Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is n ....Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is not known whether inhibiting aggrecanases is sufficient to block cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after damage to the collagen scaffold. These studies propose that clipping of the collagen scaffold may initiate aggrecan release; with progressive degeneration and collagen clipping, more aggrecan is lost, until ultimately the scaffold is severely damaged and aggrecan is severely depleted. Cartilage can only withstand a limited degree of collagen degradation and any significant damage to the network is widely considered to be irreparable. It is unclear what role aggrecanases and collagenases have in initiating and perpetuating cartilage damage. We have mice with aggrecan resistant to aggrecanases and mice with inactive aggrecanase. We will also create mice with collagen resistant to collagenase. We will use these mice to determine the contribution of collagenases and aggrecanases to the initiation and progression of cartilage damage, in three models of joint disease. We will identify differences in time of disease onset, rate of disease progression and disease severity. The results will show whether one or both activities is important for the initiation and progression of joint disease. This will reveal whether single or combination therapies are required for the management of arthritis. The research will inform the pharmaceutical industry on directions for the development of new drugs to prevent joint disease.Read moreRead less
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
Lung cancer is the most frequent cause of cancer deaths in many Western countries, including ours. Lung cancer is the third leading cause of death of Australians and the fifth leading cause of burden of disease in Australia. With exposure to cancer-causing agents such as cigarette smoke, parts of the lung may suffer permanent damage that increases the risk of lung cancer. Many of these changes include the genes in air passages and lung tissue. A certain change (called methylation) affects some g ....Lung cancer is the most frequent cause of cancer deaths in many Western countries, including ours. Lung cancer is the third leading cause of death of Australians and the fifth leading cause of burden of disease in Australia. With exposure to cancer-causing agents such as cigarette smoke, parts of the lung may suffer permanent damage that increases the risk of lung cancer. Many of these changes include the genes in air passages and lung tissue. A certain change (called methylation) affects some genes in the lungs, but it is not yet known how common this change is or how it affects smokers and people who have developed lung cancer. We will collect blood and sputum specimens from lung cancer patients to test to see if methylation is present, and also specimens from when patients have a routine bronchoscopy as part of their initial tests. If they have an operation for lung cancer, then the part of the lung that is removed and not needed for diagnosis will also be tested for methylation. In this study, we will study whether methylation is an accurate test for lung cancer, whether it is present in parts of the lung near from the lung cancer, and whether it predicts better or worse results after treatment. We hope that this research study will provide new information about the diagnosis and treatment of lung cancer.Read moreRead less
The Role Of The Cytokine Receptor Gp130 In Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Prostate cancer is a leading cause of cancer deaths in men in the Western world. Neuroendocrine cells may play an important role in the development of these cancers, but their biology is essentially uncharacterized. Activation of the cell-bound protein gp130 results in neuroendocrine differentiation, growth and chemotherapeutic drug resistance of prostate cancer cells. We will use gp130-dependent differentiation to understand how neuroendocrine cells influence normal and cancerous prostate cells ....Prostate cancer is a leading cause of cancer deaths in men in the Western world. Neuroendocrine cells may play an important role in the development of these cancers, but their biology is essentially uncharacterized. Activation of the cell-bound protein gp130 results in neuroendocrine differentiation, growth and chemotherapeutic drug resistance of prostate cancer cells. We will use gp130-dependent differentiation to understand how neuroendocrine cells influence normal and cancerous prostate cells, and to identify neuroendocrine-cell specific genes that may be of diagnostic or therapeutic benefit in prostate cancer. Gp130 can be activated by a group of hormones called the interleukin-6 type cytokines in the presence of certain cell-bound proteins (receptors). If these receptors are inappropriately expressed in the prostate, inappropriate activation of gp130 could occur resulting in prostate cancer cell growth or neuroendocrine differentiation. If we can determine that these receptors are expressed in prostate cancer, but not in non-cancerous prostate, this would have diagnostic or therapeutic benefit.Read moreRead less
In this project we aim to define the role of the Siah proteins in tumour angiogenesis and inflammatory responses. Hypoxia, a decrease in oxygen tension, places constrains on tumour growth where access to oxygen is yet to be established via new blood vessel formation. In addition hypoxia is common in areas of inflammation and wound healing, where blood vessels have been shut down to help in recovery. With the use of our Siah knockout mice we have a unique model that allows us, for the first time, ....In this project we aim to define the role of the Siah proteins in tumour angiogenesis and inflammatory responses. Hypoxia, a decrease in oxygen tension, places constrains on tumour growth where access to oxygen is yet to be established via new blood vessel formation. In addition hypoxia is common in areas of inflammation and wound healing, where blood vessels have been shut down to help in recovery. With the use of our Siah knockout mice we have a unique model that allows us, for the first time, to investigate the role of Siah in the hypoxia signalling cascade. How cells sense and react to low oxygen levels is complex and involves several proteins. A key protein is called Hypoxia induced factor, Hif-1. It accumulates under hypoxia and is responsible for the expression of genes enabling the cell to tolerate and function under hypoxic conditions. tolerate and function under hypoxic conditions, which is involved in new blood vessel formation. PHD protein directs the degradation of Hif1, while Siah directs the degradation of PHD, when oxygen is limiting. Loss of Siah proteins (eg in our knockout models) leads to an increase in PHD proteins under hypoxia thus no stabilisation of Hif-1 and impaired response to hypoxia. Thus, sitting on the top of a cascade, which controls the trashing of proteins in the cell (focus of this year's Nobel price for medicine), Siah has primary control on the response to oxygen deprivation. The relative immunity of multicellular organisms to acquired defects is through redundancy. Oxygen is a unique case, for which organisms can not bypass the defect via redundancy, making it an attractive target for future therapy. Therefore, understanding the molecular and cellular response to hypoxia may allow us to identify key molecules which could be targeted for the development of novel anti inflammatory and cancer drugs. The scope of this study is to understand the key role of Siah utilising our knockout mice in models of inflammation and cancer.Read moreRead less