The Role Of 'Orphan' Transporters In Bone Homeostasis And Disease
Funder
National Health and Medical Research Council
Funding Amount
$675,668.00
Summary
Osteoclasts (OCs) are giant multinucleated cells exclusively responsible for physiological bone degradation (resorption). Excessive OC activity leads to localised bone destruction (osteolysis) as observed in patients with osteoarthritis and underlies decreased bone mass and fragility fractures that are a hallmark of osteoporosis. This project examines the role of an orphan solute carrier transporter in OC function and its potential involvement in bone disease.
To Biochemically Trick P-Glycoprotein (Pgp) To Target Resistance Via Lysosomal Pgp
Funder
National Health and Medical Research Council
Funding Amount
$603,848.00
Summary
We have discovered an innovative biochemical strategy whereby our novel compounds exploit and trick a part of the detoxification machinery, that is the transporter, P-glycoprotein, to specifically kill drug resistant cancer cells. Herein, we take advantage of this biochemical mechanism to design novel and safe drugs to selectively target resistant tumours.
Isoprenoids, Neuromelanin And Neuronal Vulnerability In Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$538,764.00
Summary
Parkinson's disease is a common and ultimately fatal brain disease which affects primarily normal movement. While a comparatively modest cell death occurs in other areas of the brain in Parkinson's disease, the motor symptoms result from the massive death of particular brain cells which are unique in that they contain a pigment called neuromelanin. This project aims to discover what makes the neuromelanin-containing cells of the brain particularly vulnerable to cell death in Parkinson's disease. ....Parkinson's disease is a common and ultimately fatal brain disease which affects primarily normal movement. While a comparatively modest cell death occurs in other areas of the brain in Parkinson's disease, the motor symptoms result from the massive death of particular brain cells which are unique in that they contain a pigment called neuromelanin. This project aims to discover what makes the neuromelanin-containing cells of the brain particularly vulnerable to cell death in Parkinson's disease. We recently found that neuromelanin pigment in the cells of people who have died with Parkinson's disease concentrate a fat-binding protein called alpha-synuclein which is thought to be important in causing cell death in Parkinson's disease. This association between the neuromelanin pigment and alpha-synuclein was not found in other cells in Parkinson brain which do not contain pigment, nor in the brains of healthy people. We also found that a third of neuromelanin is made up of a special group of fats called isoprenoids. Changes in these fats have already been reported in the blood in Parkinson's disease. We suggest that specific changes in the isoprenoid fats in neuromelanin in Parkinson's disease cause alpha-synuclein protein to accumulate on the fat in the pigment, as well as other cellular changes which are detrimental to the cell, ultimately leading to the death of the cell. These changes may explain for the first time why neuromelanin-containing brain cells are especially vulnerable in Parkinson's disease and provide new avenues for treating this disorder.Read moreRead less
Role Of Lysosomal Acid Lipase In Regulating Insulin Secretion
Funder
National Health and Medical Research Council
Funding Amount
$570,928.00
Summary
Type 2 diabetes (T2D) affects 7% of Australians and is a major cause of morbidity and mortality. A failure of insulin secretion contributes to T2D, and this is linked to the inability of insulin producing ?-cells to use lipids appropriately (lipotoxicity). Here we will study the role of a cellular body called the lysosome to regulate ?-cell lipid metabolism and insulin secretion. This work will greatly increase the understanding of ?-cell failure in T2D.
Macrophages are important cells at the front-line of immunity where one of their main roles is to release anti-bacterial proteins. We will study the macrophage molecules, subcellular organelles and pathways that help to release these proteins to kill bacteria and fight infection. Our studies will identify new cellular targets for boosting immunity and treating inherited diseases with defective macrophage function.
Interactions Between HIV And Mycobacterial Infections Of Macrophages Mediated By Changes In Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$119,625.00
Summary
HIV-AIDS and tuberculosis are two of the worlds most important diseases. HIV-AIDS is the fourth leading killing disease worldwide and tuberculosis is the leading opportunistic infection in patients with AIDS particularly in the developing world. Both microbes infect the same cell type, the macrophage, which is widely distributed throughout the body, particularly in lymph nodes and lung. Recent studies in humans have shown that HIV and TB like organisms stimulate each others growth. This study us ....HIV-AIDS and tuberculosis are two of the worlds most important diseases. HIV-AIDS is the fourth leading killing disease worldwide and tuberculosis is the leading opportunistic infection in patients with AIDS particularly in the developing world. Both microbes infect the same cell type, the macrophage, which is widely distributed throughout the body, particularly in lymph nodes and lung. Recent studies in humans have shown that HIV and TB like organisms stimulate each others growth. This study uses the immense power of DNA microarrays, based on the identification of almost all genes by the human genome project, to decipher the interactions between the two microbes. By following up new leads indicated by the microarrays, the way in which the microbes manipulate the macrophage to enhance their own growth and that of the other can be eventually deciphered. This will provide new strategies for future interventions. New drugs are urgently needed for both microbes.Read moreRead less
Molecular Regulation Of The Serine-Threonine Kinase ULK1 In Autophagy
Funder
National Health and Medical Research Council
Funding Amount
$299,431.00
Summary
Autophagy or self eating is a basic cellular process and can have either beneficial or adverse effects in cancer. It is essential to determine the status of autophagy in patients before considering drugs that block autophagy for therapy. A protein called ULK1 is needed for autophagy and may emerge as a pathological marker for autophagy in cancer as well as a potential drug target. This grant proposal will study ULK1 regulation and will lay the scientific foundation for its medical application.
Sorting Nexins And Their Role In Endosomal Trafficking
Funder
National Health and Medical Research Council
Funding Amount
$331,000.00
Summary
Cells are able to internalise molecules via membrane-bound vesicles, a process known as endocytosis. Endocytosis is fundamental for many cellular processes, including receptor signalling, uptake of many essential nutrients and the ability to mount an effective lymphocyte response to foreign antigens. Once internalised, cargo is then sorted to different intracellular destinations of the endosomal transport system. The ultimate destination depends on the particular cargo molecule. The importance o ....Cells are able to internalise molecules via membrane-bound vesicles, a process known as endocytosis. Endocytosis is fundamental for many cellular processes, including receptor signalling, uptake of many essential nutrients and the ability to mount an effective lymphocyte response to foreign antigens. Once internalised, cargo is then sorted to different intracellular destinations of the endosomal transport system. The ultimate destination depends on the particular cargo molecule. The importance of the endosomal transport system is also highlighted by the discovery that many human diseases, including various cancers, lysosomal storage diseases and hypercholesterolemia, are linked to defects in trafficking along the endocytic pathway. Furthermore, a number of viral pathogens, such as HIV, and toxins, such as shiga toxin, exploit the endosomal system to gain entry into a cell. Understanding the molecular details of the sorting events within the endosomal system is necessary to be able to consider therapeutic manipulation of the trafficking of specific cargo molecules. The study seeks to understand the molecular details of the endosomal sorting machinery, knowledge that will underpin future efforts to develop drugs to manipulate movement of proteins within the endosomal system. In the long term, this could allow for the manipulation of a variety of cellular functions including the inhibition of proliferative signals in tumour cells.Read moreRead less
Mechanisms Of HIV Binding, Uptake, Trafficking And Infection In Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$144,250.00
Summary
HIV is the fourth greatest killing disease in the world. Currently there are more than 40 million people infected with the virus and it is spreading through Asia, especially India and China. The priorities are vaccines and new antiviral strategies to complement the existing ones and provide alternatives in the event of toxicity and viral resistance to existing drugs. HIV infects three types of body cells, CD4 lymphocytes, macrophages and dendritic cells. Dendritic cells are the key cells which n ....HIV is the fourth greatest killing disease in the world. Currently there are more than 40 million people infected with the virus and it is spreading through Asia, especially India and China. The priorities are vaccines and new antiviral strategies to complement the existing ones and provide alternatives in the event of toxicity and viral resistance to existing drugs. HIV infects three types of body cells, CD4 lymphocytes, macrophages and dendritic cells. Dendritic cells are the key cells which normally act as sentinels at the surfaces of the body picking up microbes digesting them and transferring their products to lymph nodes where the immune response is stimulated. HIV uses this pathway to enter the body and particularly to enter CD4 lymphocytes and lymph nodes and undergo explosive replication. This project is aimed at identifying new proteins which the virus uses to bind to these cells and also the pathways which the virus uses within the cells to be transferred to CD4 lymphocytes. Such knowledge should allow the design of new antiviral strategies and may also assist in developing HIV vaccines.Read moreRead less