Parathyroid Tumorigenesis - A Role For The Newly Identified Putative Tumour Suppressor HRPT2
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Primary hyperparathyroidism is one of the most common tumour associated diseases of hormone secreting glands affecting 0.1-0.5% of adults and up to 3.4% of post-menopausal women. It can occur in family members, either alone or with other tumours, and can also occur with no family history (sporadic). Hyperparathyroidism is caused by secretion of excessive levels of parathyroid hormone. Amongst other problems, this causes significant bone disease that can lead to fracture. What is going wrong at t ....Primary hyperparathyroidism is one of the most common tumour associated diseases of hormone secreting glands affecting 0.1-0.5% of adults and up to 3.4% of post-menopausal women. It can occur in family members, either alone or with other tumours, and can also occur with no family history (sporadic). Hyperparathyroidism is caused by secretion of excessive levels of parathyroid hormone. Amongst other problems, this causes significant bone disease that can lead to fracture. What is going wrong at the genetic level to cause this disease is, in most cases, poorly understood. In Hyperparathyroidism Jaw Tumour Syndrome (HPT-JT), one form of familial hyperparathyroidism, we and our international collaborators have recently identified mutations in the gene HRPT2 predicted to lead to loss of function of this gene. HRPT2 has no known similarities to other genes that may give hints as to its function. The overall aim of this project is to test our theory that HRPT2 has an important role in abnormal growth of parathyroid tissue that, in some cases, will lead to cancer. Further, we hypothesise that this gene will have a role in both familial and sporadic presentations of parathyroid disease. We will investigate this gene in parathyroid tumour specimens from patients with familial and sporadic disease for gene mutations and also different levels of gene expression. We will also explore a mechanism for how these mutations may function to cause disease and look at the effect of reduced HRPT2 expression on expression of thousands of other genes using a technique known as microarray analysis. The expected outcomes of this study include the identification of individuals at risk of developing cancer whose treatment will be tailored to their genetic profile. Characterisation of HRPT2, and the genes its expression influence, may lead to the identification of suitable targets for future treatment of hyperparathyroidism and its effects on bone disease.Read moreRead less
Falls and broken bones are costly health problems among the elderly, even more so when there is a growing older population aged over 65 years. In Australia about 1 million older people have at least one fall each year and about 40-60% will sustain major injuries including broken bones. Therefore there is a need to identify effective ways to reduce falls and improve outcomes of those who break a bone, especially of the hip.
Gene Variants Related To Bone Density And Fracture.
Funder
National Health and Medical Research Council
Funding Amount
$330,375.00
Summary
Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene. The gene is a master regulator of the cells that mak ....Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene. The gene is a master regulator of the cells that make bone: this gives hope that it may be possible to alter bone formation through this master regulator.Read moreRead less
Orthopaedic medicine utilises precise control of critical aspects of the bone healing response. This proposal looks at a novel, and powerful neural-based method for controlling these processes. This will be done by modulating the activity of the neuropeptide Y1 receptor, recently identified on osteoblastic cells and capable of powerful, inverse regulation of bone formation activity. Harnessing these effects will provide a critical tool for existing surgical practice.
Value Of Androgen Deprivation And Bisphosphonate Therapy In Patients Treated By Radiotherapy For Limited Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$1,757,375.00
Summary
Prostate cancer depends for its growth on the male hormone, testosterone, which circulates in the blood. As a result treatment which reduces testosterone level ('androgen deprivation'[AD] therapy) can produce clinically important shrinkage of prostate cancer. Each year approximately 4000 men in Australia and New Zealand develop prostate cancer which has not spread widely and which is amenable to attempted cure by surgery or radiation. Results from recent trials, including a large trial run in Au ....Prostate cancer depends for its growth on the male hormone, testosterone, which circulates in the blood. As a result treatment which reduces testosterone level ('androgen deprivation'[AD] therapy) can produce clinically important shrinkage of prostate cancer. Each year approximately 4000 men in Australia and New Zealand develop prostate cancer which has not spread widely and which is amenable to attempted cure by surgery or radiation. Results from recent trials, including a large trial run in Australia and New Zealand by the Trans-Tasman Radiation Oncology Group (TROG) between 1996 and 2000, suggest that 6 months AD will benefit many of these men if administered in conjunction with radiotherapy.The aim of this project is to run a further trial to find out whether 12 months of AD, after radiotherapy will prevent the need for further treatment and prolong more lives than only 6 months AD. Bisphosphonate treatment also offers important benefits to prostate cancer patients because it can increase bony stregth by increasing its density and can also arrest cancerous growth in bones. A further aim of the trial therefore is to determine whether 18 months of bisphosphonate therapy (BP) will prevent bone loss (osteoporosis) caused by AD, and also further reduce the risk of secondary bone cancer developing. This trial will involve recruitment of 1000 men across Australia and New Zealand over a 5 year period. When complete the trial will determine whether further treatment can be delayed and life prolonged in up to half of all men in whom treatment presently fails. This grant will support collection of patient data and the necessary quality checks to ensure that reliable conclusions can be drawn.Read moreRead less
The Role Of The Secreted SVS7 Protein In Bone Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$605,122.00
Summary
Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue leading to bone fragility and an increased susceptibility to fractures caused by imbalance between cells that are constantly reabsorbing and reforming bone. The cost to society with our aging population and individuals who become disabled by hip fractures could triple by the year 2040.The proposed project studies a novel factor that controls bone mass. Its potential is for therapeutic treatment.
Interaction Between PTH And Y2 Bone Anabolic Pathways
Funder
National Health and Medical Research Council
Funding Amount
$731,311.00
Summary
Osteoporosis is a costly condition that affects more than 150 million people worldwide and fills more hospital beds than any other disease*. People who have osteoporotic fractures experience a diminished quality of life and a reduced life expectancy. Although there are currently a number of therapies in use to reduce further loss of bone in osteoporotic patients, there is only one to replace lost bone, parathyroid hormone. For clinical and economic reasons, there is a need for additional bone-bu ....Osteoporosis is a costly condition that affects more than 150 million people worldwide and fills more hospital beds than any other disease*. People who have osteoporotic fractures experience a diminished quality of life and a reduced life expectancy. Although there are currently a number of therapies in use to reduce further loss of bone in osteoporotic patients, there is only one to replace lost bone, parathyroid hormone. For clinical and economic reasons, there is a need for additional bone-building therapies. Like all tissues, the nervous system affects skeletal function. We recently discovered a powerful control pathway by which the nervous system regulates bone formation. This project will test whether altering the function of this neural pathway can increase bone formation and whether it can work together with parathyroid hormone therapy to produce an enhanced bone formation response greater than either therapy alone. This research is important because of the need for new osteoporosis therapies to repair weakened bones. The knowledge gained from this study has the potential to provide a very important and useful contribution to skeletal health and thus aged health worldwide. *The Burden of Brittle Bones: Costing Osteoporosis in Australia. A report prepared by Access Economics Pty. Ltd. September 2001Read moreRead less
Role Of The Osteoclast In Endochondral Fracture Repair
Funder
National Health and Medical Research Council
Funding Amount
$310,136.00
Summary
Failure of bone healing leads to significant pain and disability, such that augmentation of fracture repair is a dynamic and important field of study. A full understanding of bone repair is necessary before we can hope to introduce successful therapies. We theorise that by stimulating bone forming cells and inhibiting bone resorbing cells we may be able to provide optimal results. Bone resorbing cells, or osteoclasts, have long been considered essential to the initial stages of bone repair (endo ....Failure of bone healing leads to significant pain and disability, such that augmentation of fracture repair is a dynamic and important field of study. A full understanding of bone repair is necessary before we can hope to introduce successful therapies. We theorise that by stimulating bone forming cells and inhibiting bone resorbing cells we may be able to provide optimal results. Bone resorbing cells, or osteoclasts, have long been considered essential to the initial stages of bone repair (endochondral ossification) during which the early soft cartilaginous callus is replaced by hard mineralised callus. Our preliminary studies lead us to believe that endochondral ossification can indeed proceed without osteoclast activity. If we can safely eliminate osteoclast function early in the early stages of fracture repair, a number of therapeutic options open up for the augmentation of bone healing. The return of osteoclast function is necessary in the long term, so our strategy will also need to take this into account. This study will establish which systems are pivotal in endochondral ossification and therefore which interventions we should explore.Read moreRead less