Exploring The Therapeutic Potential Of TRAIL In Diabetes And The Metabolic Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$446,374.00
Summary
TNF-related apoptosis-inducing ligand (TRAIL) is a protein with potentially useful actions in human health and disease. TRAIL is able to prevent atherosclerosis, the cause of heart attacks and strokes. In addition, we have recently shown that its actions on fat and the pancreas may prevent the development of the metabolic syndrome and type 2 diabetes. These studies will explore the therapeutic potential of TRAIL for the prevention of diabetes and heart disease in a range of animal models.
Regulation Of Bone Resorption In Periodontal Disease
Funder
National Health and Medical Research Council
Funding Amount
$258,500.00
Summary
Periodontal disease is the most common disease involving bone loss in the world. We know little about the causes and how the disease develops. Some of the bacteria that live in the mouth are associated with the disease but the presence of these bacteria does not mean a person will have it. We do not know why some people suffer from the disease and others do not. Unfortunately when a person has periodontal disease the dentist has few choices in the way in which the patient is treated. There are n ....Periodontal disease is the most common disease involving bone loss in the world. We know little about the causes and how the disease develops. Some of the bacteria that live in the mouth are associated with the disease but the presence of these bacteria does not mean a person will have it. We do not know why some people suffer from the disease and others do not. Unfortunately when a person has periodontal disease the dentist has few choices in the way in which the patient is treated. There are no drugs presently available to treat this disease and surgical removal of the diseased tissue is the only option for treatment. Often after this treatment the disease continues to get worse and more bone is lost sometimes resulting in the loss of teeth. This study aims to understand how the disease causes the bone loss. We believe that some newly identified factors that regulate the cells which destroy bone are responsible. Our recently works show that these factors are present in abnormal levels in the diseased tissues of patients. We also wish to go further and try and find ways of treating the disease. We aim to find new treatments based on controlling the factors that regulate the cells that destroy bone .Read moreRead less
We have found that leptin, a new hormone produced by fat cells which regulates appetite and metabolism, is a powerful inhibitor of osteoclast formation. Osteoclasts are large cells present in bone which are responsible for bone resorption and therefore these cells contribute to common bone conditions such as osteoporosis, Paget's disease and bone cancer. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. Persons wh ....We have found that leptin, a new hormone produced by fat cells which regulates appetite and metabolism, is a powerful inhibitor of osteoclast formation. Osteoclasts are large cells present in bone which are responsible for bone resorption and therefore these cells contribute to common bone conditions such as osteoporosis, Paget's disease and bone cancer. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. Persons who are overweight tend to have higher circulating blood levels of leptin and also tend to have denser bones, which suggests that there might be a relationship between blood leptin and bone density or strength. Furthermore, leptin is produced in the bone marrow which is where osteoclasts are produced. Osteoclasts are formed from white blood cells which are present in the bone marrow and the blood. Very recent discoveries have identified a family of new factors which play a key role in the formation of osteoclasts. One of these factors has been called osteoprotegerin and is an inhibitor of osteoclast formation. Mutant mice lacking osteoprotegerin have greatly increased numbers of osteoclasts and severe osteoporosis whereas mutants with too much osteoprotegerin have bones which are much denser than normal. The availability of these factors now allows the generation of human osteoclasts in the laboratory which enables the further study of how the process is regulated. We have found that leptin increases the amount of osteoprotegerin produced by white blood cells and we believe that this is the major way that leptin inhibits osteoclast generation. In this project, we intend to further investigate how and why leptin is able to influence the generation and function of osteoclasts as leptin may be a suitable treatment for osteoporosis and other bone diseases.Read moreRead less
Role Of Osteoprotegerin In Protecting The Diabetic Aorta From Aneurysm Formation
Funder
National Health and Medical Research Council
Funding Amount
$299,250.00
Summary
Between 5% and 10% of men over the age of 60 years develop weakening of their main abdominal artery (aorta) leading to slow dilation of the vessel. If this process continues long term the artery can burst resulting in sudden death. At present the only treatment available for this problem is surgery, either open or minimally invasive. Both these forms of treatment are associated with significant complications and unsuitable for some patients. Thus the development of a drug treatment which can slo ....Between 5% and 10% of men over the age of 60 years develop weakening of their main abdominal artery (aorta) leading to slow dilation of the vessel. If this process continues long term the artery can burst resulting in sudden death. At present the only treatment available for this problem is surgery, either open or minimally invasive. Both these forms of treatment are associated with significant complications and unsuitable for some patients. Thus the development of a drug treatment which can slow or halt the weakening and dilation of the aorta would have great patient benefits'. Surprisingly patients with sugar diabetes are less likely to develop this form of artery weakening. This important negative association may form the basis of discovering a new medication to protect arteries from rupture. In this study we investigate the role of a recently discovered protein in protecting the main abdominal artery from weakening in diabetics. This protein is of particular interest for the following reasons: 1. It comes from a group of proteins believed to be important in artery calcium build-up. 2. Artery calcium is common in patients with diabetes who are relatively protected from aortic weakening. 3. It is being used for the treatment of bone weakening, appears to be safe in patients and therefore is a potential therapeutic agent. We believe this work is an important step towards the development of a successful medical treatment for artery weakening.Read moreRead less
Structural And Functional Analyses Of Rat Receptor Activator Of NF-kb Ligand
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Rat RANKL (Xu and Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption. This process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fra ....Rat RANKL (Xu and Zheng, rat RANKL, AustraliaProvisional Patent PQ3147) has a variety of biological activities including osteoclast differentiation and polarization, and dendritic cell function. Overproduction or increased activity of RANKL can result in excessive osteoclast formation, activation, and bone resorption. This process contributes to many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic diseases, arthritis, aseptic bone loosening and non-union of fractures. This proposal addresses the important and fundamental issue of RANKL regarding the role of molecular structure on its biological function. We have established that the TNF-like core domain is the functional domain, important for osteoclastogenesis, osteoclast polarisation and protecting against Fas-triggered apoptosis. This proposal will further characterise the mutant forms of the TNF-like core domain of RANKL using site directed mutagenesis and protein truncation analysis, and assess their respective binding activities to OPG and RANK, and their biological activities both in vitro and in vivo. It will lead us into better understanding of the structure-function relationship of RANKL. Ideally, we would like to develop a relative agent for the suppression of osteolysis in orthopaedic related diseases including osteoporosis. Such an optimized molecule could become a potent therapeutic agent that selectively inhibits osteoclast formation and bone resorption.Read moreRead less
Breast Cancer has a particular preference to form cancer metastases in bone where its presence is associated with bone destruction that frequently results in significant pain and disability. Bone seems to provide a fertile soil for breast cancer cells that have moved into the blood vessels from the original cancer site in the breast. Once tumour cells have invade bone marrow spaces from the blood vessels they are able to grow and induce the normal cells of the bone marrow to destroy the surround ....Breast Cancer has a particular preference to form cancer metastases in bone where its presence is associated with bone destruction that frequently results in significant pain and disability. Bone seems to provide a fertile soil for breast cancer cells that have moved into the blood vessels from the original cancer site in the breast. Once tumour cells have invade bone marrow spaces from the blood vessels they are able to grow and induce the normal cells of the bone marrow to destroy the surrounding hard bone. This allows the tumour to grow faster. Together these processed create a vicious cycle that contributes to the serious consequences of bone metastases. In this project we will be studying mice with breast cancer to understand what makes the bone marrow such a fertile and receptive site for breast cancer metastasis. In particular, we are looking at how the normal processes of bone renewal and repair contribute to the establishment of cancer in bone. We will use the body's own bone protecting protein, called osteoprotegerin, to test how blocking bone destruction will affect the ability of cancer cells to invade and grow in bone. This study has the potential to change the way bone metastases are treated. Treatment of breast cancer could be significantly improved if the fertile soil of bone could be modified to either block the targeting of breast cancer to bone, or to inhibit its growth there.Read moreRead less