Molecular Characterisation Of The Dendritic Cell Receptor Clec9a And Its Ligand Interactions
Funder
National Health and Medical Research Council
Funding Amount
$651,784.00
Summary
The immune system senses danger from infectious diseases, damaged and dead cells. We identified a danger receptor, Clec9A, on a specialised cell type of the immune system in mice and humans. Clec9A recognizes and induces immunity to dangerous dead cells. Delivering vaccines to Clec9A improves vaccine responses. We will investigate how Clec9A recognises and reacts to danger, and how we can mimic this recognition to improve vaccine design.
Characterisation Of The Role & Biomarker Potential Of The Novel Cell Surface Protein TTYH2 In Renal Cell Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Renal cell carcinoma is the most common cancer of the kidney. One-third of patients upon first diagnosis have secondary tumour sites already within their body as well as new treatment approaches for more advanced disease making them very difficult to cure. An early specific test for this cancer is urgently needed. Our group has identified a new gene called TTYH2 which is highly expressed by renal cell carcinoma tissue samples but not in normal kidney tissues. In this study, we intend to look at ....Renal cell carcinoma is the most common cancer of the kidney. One-third of patients upon first diagnosis have secondary tumour sites already within their body as well as new treatment approaches for more advanced disease making them very difficult to cure. An early specific test for this cancer is urgently needed. Our group has identified a new gene called TTYH2 which is highly expressed by renal cell carcinoma tissue samples but not in normal kidney tissues. In this study, we intend to look at the expression of TTYH2 in more clinical samples to determine if TTYH2 will be a useful bio-marker for this cancer. We are also studying the function of this protein in renal cell carcinoma cells to identify the exact role that TTYH2 performs in cancer development and progression. Finally we will look at what other proteins are interacting with TTYH2 in kidney cancer cells. These latter studies will help us to understand the disease process better and may help us design new treatment methods.Read moreRead less
Molecular Characterization Of The Gingipains Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$394,000.00
Summary
Chronic periodontitis is a bacteria-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. The bacterium Porphyromonas gingivalis has now been identified as a major pathogen in the development of chronic perio ....Chronic periodontitis is a bacteria-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. The bacterium Porphyromonas gingivalis has now been identified as a major pathogen in the development of chronic periodontitis. We have identified a major virulence factor of P. gingivalis which is an extracellular complex of proteins involved in binding and destroying host proteins. The aim of this proposal is to characterize the secretion, molecular processing and assembly of the cell surface complex using state-of-the-art proteomic techniques. This study will provide valuable insight into the molecular processes of a bacterial pathogen that leads to virulence. Detailed knowledge on the unique molecular events involved in secretion, processing and assembly of a major virulence factor will provide molecular targets for the development of specific inhibitors that may have utility as an adjunctive therapeutic and-or as part of a preventive regime or maintenance program for the control of chronic periodontitis. Further, the molecular insight that will result from this study will have broader application in the understanding of virulence factor processing of a Gram-negative pathogen that will provide paradigms for other bacterial pathogens.Read moreRead less
OVARIAN CANCER METASTASIS: Unraveling The Biology Of The Plasminogen Activation Cascade
Funder
National Health and Medical Research Council
Funding Amount
$169,875.00
Summary
Ovarian cancer affects 1,200 new Australians every year. Compared to breast cancer where research education and early screening have improved mortality rates, the incidence of ovarian cancer has not improved and death rates have more than doubled since 1930. With few overt symptoms, ovarian cancer has an extremely poor prognosis - a staggering 71% of women diagnosed with ovarian cancer will die from the disease, compared to 21% for breast cancer. Any studies which increase our understanding of t ....Ovarian cancer affects 1,200 new Australians every year. Compared to breast cancer where research education and early screening have improved mortality rates, the incidence of ovarian cancer has not improved and death rates have more than doubled since 1930. With few overt symptoms, ovarian cancer has an extremely poor prognosis - a staggering 71% of women diagnosed with ovarian cancer will die from the disease, compared to 21% for breast cancer. Any studies which increase our understanding of the biology of ovarian cancer metastasis may lead to new therapies designed to control these processes - as such this would be a major inroad into our fight against this cancer. The aim of this novel research project is to unravel the role that one cell surface system (the plasminogen (Plg) activation cascade) plays in determining the ability of ovarian cancer cells to metastasise and regulate new tumour blood vessel formation. This study addresses the paradoxical observations that this cascade can simultaneously facilitate cancer metastasis whilst concomitantly stopping new blood vessel formation in tumours. Using a number of advanced molecular cell biology methods, the hypothesis we will test is that the capacity of ovarian cancer to metastasise is determined by differential processing of plasminogen subsequent to cell-surface Plg binding. This results in a delicate balance between the generation of cell surface proteases and the release of protein fragments capable of stopping tumour blood vessel growth. Our group is well-equipped to address this hypothesis since we have already shown that: (1) Plg binding and activation is required for cancer cell invasion; (2) Plg binding and activation is elevated on malignant compared to benign cancers (3) Plg unfolds after it binds to cell surfaces or recombinant receptors; and, (4) Plg is easily fragmented to products that inhibit new blood vessel formation after binding to some cancer cells.Read moreRead less
The hormone angiotensin II affect our heart and blood vessels by switching-on receptors that are then switched-off to prevent over-stimulation. This application continues our investigations into how angiotensin II receptors are switched-on and -off. We apply new technologies to identify and study receptor modulating proteins and the pairing receptors into dimers. Results will further our understanding of angiotensin receptors and cardiovascular control.
The Regulation Of Pleiotropic Responses By Phospho-Ser/Tyr Binary Switches Embedded In Growth Factor Receptors
Funder
National Health and Medical Research Council
Funding Amount
$349,190.00
Summary
Cells in the body are able to accomplish an impressive range of functions within their lifetime. Underlying this diversity in cellular functions are a quorum of fundamental cellular responses that include cell survival, cell proliferation (growth) and cell differentiation (commitment to a more mature cell identity). Diffusible factors (called growth factors) are important in regulating these cellular responses. This is achieved through growth factor binding to specific proteins (called receptors ....Cells in the body are able to accomplish an impressive range of functions within their lifetime. Underlying this diversity in cellular functions are a quorum of fundamental cellular responses that include cell survival, cell proliferation (growth) and cell differentiation (commitment to a more mature cell identity). Diffusible factors (called growth factors) are important in regulating these cellular responses. This is achieved through growth factor binding to specific proteins (called receptors) on the surface of cells which in turn activate signalling cascades that convey messages within the cell instructing a specific response. We have identified a new mechanism that allows a growth factor receptor to convert analogue inputs (in the form of growth factor stimulation) to a digital output (where a cell responds in a decisive fashion). This analogue-to-digital conversion is encoded by a molecular switch embedded in growth factor receptors that toggles between two alternate positions to promote either cell survival alone or cell survival as well as cell differentiation-proliferation. In this manner, these molecular switches have binary (either-or) characteristics and provide a new explanation for the independent regulation and coordination of different cell functions. These findings have implications for understanding how specific cellular responses such as cell survival, proliferation and differentiation can be regulated and perhaps harnessed to improve tissue regeneration after damage (e.g. in stroke, heart attack trauma) or in understanding how things go wrong in diseases such as cancer where cell survival, proliferation and differentiation become deregulatedRead moreRead less