Molecular Markers Of The Progression Of Intestinal Metaplasia To Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$556,618.00
Summary
Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characteri ....Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characterised by genetic events that are largely unknown and occur over a period that can take years. It is also evident, especially in countries where GC is not as prevalent, that only a proportion of individuals will eventually develop GC. The long latency from the develpoment of IM and diagnosis of GC offers an opportunity to intervene and study the changes that lead to GC as well as find genes that may predict which individuals will progress. IM is the stage in which intervention is obvious. It is very easily diagnosed, is present for a long time and, for certain individuals, will eventually accumulate enough genetic events that will mandate progression to GC. Targeted screening of these individuals will enable a feasible strategy to find early GC, and avoid costly non-targeted screening. This proposal seeks to find key genetic events responsible for the transition of IM to GC. The first step utilises Affymetrix arrays to detect genes expressed in IM and specifically linked to GC. These candidates will be validated and used to study their role in the progression to GC using a mouse model of GC. This study is designed to find genes responsible for GC that can be used as: 1) a marker of progression in humans that will be used as a tool to stratify individuals into a screening protocol; 2) candidates to be tested in animal studies to study the pathogenesis of GC and potentially used as preventative or therapeutic targets.Read moreRead less
Antitumour Efficacy Of TRAIL: An Immunotherapeutic Approach For The Treatment Of Skeletal Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$459,034.00
Summary
The most serious clinical problem with patients with solid tumours is metastasis to bone, which leads to complications that can cause erosion of the patient's quality of life, and eventually death. TRAIL is a new cancer therapeutic that selectively kills cancer cells while sparing normal cells. The use of TRAIL agonistic antibodies that do not bind OPG and have increased serum half life offers an exciting approach for the treatment of skeletal malignancies that is non toxic and safe.
The Effect Of Metals On Neurofibrillary Tangle Formation
Funder
National Health and Medical Research Council
Funding Amount
$333,313.00
Summary
The majority of studies into Alzheimer's disease (AD) have focussed on two brain lesions- the plaque and neurofibrillary tangle (NFT), which are believed to have a causative role in AD. Our lab has made several seminal discoveries about the role that metals play in the development of plaques. We are now extending this work to evaluate the role of metals in NFT formation. These studies will provide insight into the formation and possible treatments for this primary brain lesion in AD.
Probing Developmental Causes Of Soft Tooth Enamel With Novel Mouse Models
Funder
National Health and Medical Research Council
Funding Amount
$470,112.00
Summary
Tooth decay is one of the most costly diseases in Australia and was recently called a national tragedy by the Prime Minister. The risk of decay increases if teeth don't harden properly in childhood. This project aims to clarify the causes of soft enamel and identify ways to prevent it. Two new test systems will be used to see how antibiotics and fluoride affect enamel hardening. Our findings will help the battle against tooth decay and guide the safe use of medicines in children.
Identification And Characterisation Of Mouse Models For Recessively Inherited Deafness.
Funder
National Health and Medical Research Council
Funding Amount
$691,893.00
Summary
Hearing loss affects 10% of Australians. Approximately 1 in 1000 children are born deaf. A progressive hearing impairment occurs with age so that more than 50% of people over the age of 75 have a substantial hearing loss. The financial, social and personal costs of deafness are significant. Deafness is caused by environmental and-or inherited factors. In the majority of children and young people with a hearing impairment the underlying cause is genetic. It is also known that genetic predispositi ....Hearing loss affects 10% of Australians. Approximately 1 in 1000 children are born deaf. A progressive hearing impairment occurs with age so that more than 50% of people over the age of 75 have a substantial hearing loss. The financial, social and personal costs of deafness are significant. Deafness is caused by environmental and-or inherited factors. In the majority of children and young people with a hearing impairment the underlying cause is genetic. It is also known that genetic predisposition frequently contributes to the time of onset and the severity of age-related hearing loss, as well as susceptibility to noise and ototoxic drugs. It has proven difficult to identify the genes causing deafness, especially those genes associated with age-related hearing loss and susceptibility to noise and ototoxic drugs. The mouse ear is very similar to the human ear and therefore well suited to genetic and molecular studies of human deafness. Australia has a unique resource of mutagenised mice that are being bred to uncover recessive deafness, the most common type of inherited hearing loss. We have so far identified 10 mouse strains with recessive hearing impairment. 5 of the strains have an age-related hearing loss. We have identified the genetic mutation in 3 of the strains, including a mutation in a novel deafness gene. Another strain has a mutation in a novel deafness gene yet to be identified. We propose to continue the studies of these and additional mice. We will investigate why changes in these genes cause hearing loss and determine in detail how genetic and environmental factors lead to hearing loss in young and old. The results will allow us to offer earlier diagnosis and better counselling to affected families, and in the longer term we believe our research will enable us to develop improved or novel treatments to delay or prevent deafness.Read moreRead less
The Physiological Relevance Of Calcitonin In Osteoclast Function
Funder
National Health and Medical Research Council
Funding Amount
$437,640.00
Summary
Throughout adult life, bone tissue is continuously remodelled. The two main processes involved in bone remodelling, are bone formation and bone breakdown. Bone formation is controlled by cells known as osteoblasts and bone breakdown is controlled by cells known as osteoclasts. Under normal circumstances these two processes are tightly coupled. Excessive breakdown of bone, causes these two processes to become unbalanced and results in bone loss. This is the basis of many bone diseases such as ost ....Throughout adult life, bone tissue is continuously remodelled. The two main processes involved in bone remodelling, are bone formation and bone breakdown. Bone formation is controlled by cells known as osteoblasts and bone breakdown is controlled by cells known as osteoclasts. Under normal circumstances these two processes are tightly coupled. Excessive breakdown of bone, causes these two processes to become unbalanced and results in bone loss. This is the basis of many bone diseases such as osteoporosis, a condition in which the bones become fragile and therefore more susceptible to fracture. 1 in 2 women and 1 in 5 men aged 70 years and older suffer from osteoporosis in Australia. Despite this, the mechanisms which control osteoclast breakdown of bone are not well understood. Our laboratory is interested in how hormones affect osteoclast action. We plan to examine the role of the hormone calcitonin, thought to be important inhibitor of osteoclastic bone breakdown. This will be achieved by studying transgenic mice in which the receptor for calcitonin is specifically removed from osteoclasts. This will allow us to precisely determine the role of calcitonin in osteoclast function. Current treatment for osteoporosis involves the administration of drugs which inhibit bone breakdown. This project will increase our understanding of how calcitonin acts to regulate the function of osteoclasts. We believe that this research is of great importance as osteoporosis is becoming more prevalent as the population ages.Read moreRead less
The Genetic Control Of Platelet Production And Function
Funder
National Health and Medical Research Council
Funding Amount
$558,920.00
Summary
Platelets are the tiny cells that circulate in the body and make blood clot. The human body has more than a trillion of them at any one time, and they are replaced every week by the blood producing cells that reside in the bone marrow. Keeping the normal number of platelets steady is incredibly important any significant drop can result in a life-threatening hemorrhage. The clinical name given to a low platelet count is thrombocytopenia, and it is a very common problem. It can be caused by geneti ....Platelets are the tiny cells that circulate in the body and make blood clot. The human body has more than a trillion of them at any one time, and they are replaced every week by the blood producing cells that reside in the bone marrow. Keeping the normal number of platelets steady is incredibly important any significant drop can result in a life-threatening hemorrhage. The clinical name given to a low platelet count is thrombocytopenia, and it is a very common problem. It can be caused by genetic mutations, viral infections, or by cancer treatments like chemotherapy. The only way to raise platelet numbers in a person with thrombocytopenia is a blood transfusion, which carries with it risks and potential side effects. While we understand quite a lot about how the body produces platelets, we don t know anywhere enough to be able to develop new treatments. Our work is focused on the identification of the genes that control the process, beginning with mouse models of thrombocytopenia, genome mapping, gene isolation, and finally, making the links between the newly identified genes and patients with thrombocytopenia. It will give us a much better understanding of how platelets are produced, how things go wrong in human disease, and how new therapies might be developed to treat them.Read moreRead less