Proteolytic Processing Of Alzheimer's Amyloid Precursor: Identification Of Gamma-secretase
Funder
National Health and Medical Research Council
Funding Amount
$240,581.00
Summary
Alzheimer's disease is the major cause of dementia among the elderly and affects more than 20% of the population aged 80 and over. There is no cure for the disease and the treatments currently available can only retard its progression and have serious side-effects. Examination of the brain from subjects who died from Alzheimer's disease shows lesions: these are called amyloid plaques. The plaques are formed by the abnormal accumulation of an insoluble and toxic protein which causes death of the ....Alzheimer's disease is the major cause of dementia among the elderly and affects more than 20% of the population aged 80 and over. There is no cure for the disease and the treatments currently available can only retard its progression and have serious side-effects. Examination of the brain from subjects who died from Alzheimer's disease shows lesions: these are called amyloid plaques. The plaques are formed by the abnormal accumulation of an insoluble and toxic protein which causes death of the brain cells. Some gene defects which cause Alzheimer's disease at an early age (30-60 years) are known to accelerate the accumulation of the toxic protein, thereby causing progressive degeneration of the brain. Our research is aimed at understanding at the molecular level how the toxic protein forms. We know that it is part of a large protein and that its release requires two enzyme cuts. Now we propose to isolate and characterize these enzymes and to search for drugs which will neutralize them. This constitutes a rational approach to a therapeutic strategy fo halting or slowing down the progression of Alzheimer's disease.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
Characterisation Of The Biochemical And Cell Biological Mechanisms Of Cross-presentation In Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
The immune system possesses several mechanisms to fight viruses and cancer. One of these mechanisms consists of recruiting anti-virus or anti-cancer killer cells. These killer cells are recruited by specialized cells known as Dendritic Cells (DC). The DC are distributed all over the body, and can detect the presence of viruses or cancer cells. When they do, they take up chunks of the virus or cancer cells, break them into small pieces called antigens, and display these antigens on their surface, ....The immune system possesses several mechanisms to fight viruses and cancer. One of these mechanisms consists of recruiting anti-virus or anti-cancer killer cells. These killer cells are recruited by specialized cells known as Dendritic Cells (DC). The DC are distributed all over the body, and can detect the presence of viruses or cancer cells. When they do, they take up chunks of the virus or cancer cells, break them into small pieces called antigens, and display these antigens on their surface, where they can be seen by the killer cells. This initiates an immune response whereby the killer cells seek and destroy the viruses and cancer cells. We are trying to harness the ability of DC to initiate immune responses in order to design more efficient vaccines to fight viruses and cancer. Our goal is to deliver vaccines that will directly target the DC and induce the formation of protective killer cells. These strategies require us to overcome two problems. The first is that we possess different types of DC, which play distinct functions, but we do not know which type is the most effective at recruiting killer cells, or why. The second problem is that we need to understand which vaccine design is the most effective at promoting presentation of the antigens that will be used to induce killer cells. The goal of this research project is to learn how we should deliver antigens to which DC type to generate the best possible vaccine.Read moreRead less
Designer RNA-binding Proteins For Research And Therapeutic Purposes
Funder
National Health and Medical Research Council
Funding Amount
$557,480.00
Summary
It has become clear recently that ribonucleic acids play many roles in the switching on and off of genes in humans and other organisms. These molecules play roles in a number of diseases, including HIV-AIDS, hepatitis, and a large number of inherited disorders. We propose to build a library of protein molecules that can bind specifically to a wide range of RNA targets and modulate their function. These molecules have the capacity to act as therapeutics for a wide range of diseases.
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
Mechanism Of Interaction Of VWC Domains And Consequence For Protein Function
Funder
National Health and Medical Research Council
Funding Amount
$516,803.00
Summary
More than 1000 proteins contain a type of module known as the VWC domain. These domains are discreet sections of the protein that are very important for how the protein works. Proteins containing this domain are involved in normal functioning of the human body and in diseases of the nervous system and blood, among others. The main function of the VWC domain is to link proteins together in complexes. How this is achieved is not known and is what we aim to discover.