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
Role Of The Ets Family Transcription Factor Erg In Stem Cell Function And Hematopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$413,775.00
Summary
The cells responsible for producing blood are called hematopoietic stem cells (HSCs). Our research is focused on the genes that control HSC growth and development. We have discovered that a gene known to cause cancer, Erg, plays a critical role in regulating this process. This Project will tease apart the mechanism by which it does so, provide insights into how Erg can trigger cancer, and help us understand the molecular network of regulators that control blood cell production.
The Role Of The Plasminogen Activators (PAs), Urokinase-PA And Tissue-type PA In Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Many diseases, such as rheumatoid arthritis (RA), are inflammatory by nature. Intra-articular fibrin deposition is an early and persistent hallmark of inflammatory responses, resulting from an altered balance between coagulation (the production of fibrin) and fibrinolysis (the breakdown of fibrin). This fibrin accumulation can have adverse effects in RA, including mediating and-or enhancing inflammation, and contributing to subsequent joint damage. The plasminogen activators (PA), urokinase PA ( ....Many diseases, such as rheumatoid arthritis (RA), are inflammatory by nature. Intra-articular fibrin deposition is an early and persistent hallmark of inflammatory responses, resulting from an altered balance between coagulation (the production of fibrin) and fibrinolysis (the breakdown of fibrin). This fibrin accumulation can have adverse effects in RA, including mediating and-or enhancing inflammation, and contributing to subsequent joint damage. The plasminogen activators (PA), urokinase PA (u-PA) and tissue-type PA (t-PA) convert plasminogen into plasmin which can then breakdown the accumulated fibrin. Their presence in RA patients would therefore be beneficial. However, u-PA is also implicated in cell migration leading to inflammatory cells accumulating in the joint, and cartilage destruction, both of which are detrimental to disease outcome. In the joints of RA patients there are high levels of u-PA and low levels of t-PA. We, and our collaborators, have found that in the absence of t-PA, disease is exacerbated, whilst in the absence of u-PA, the outcome depends on the type of disease, either exacerbating or ameliorating disease. This highlights the different roles u-PA can have. The current proposal aims to determine the role of u-PA in inflammation and arthritis, and whether enhancing t-PA can have beneficial outcomes with respect to disease severity. In addition, we will also study whether intra-articular fibrin deposition can, in fact, drive the inflammatory reaction and cartilage destruction seen in RA. The findings will be important for our understanding of the role of fibrin accumulation in the inflammatory and destructive processes that occur in RA, and the roles of u-PA and t-PA in enhancing and preventing them respectively. Information gained will provide clues for useful strategies for the treatment of human inflammatory diseases, including RA.Read moreRead less
Functional Analysis Of Candidate Sex-determining And Gonadal Development Genes
Funder
National Health and Medical Research Council
Funding Amount
$503,500.00
Summary
This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper development of the gonads, organs that control an individual's sexual development. It is thought that a genetic chain of events is important for gonadal development, and we aim to find the missing links of that chain and to work out how they fit together, as well as how genetic defects can lead to disorders of sexual development. Def ....This project is aimed at finding and studying the genes that control whether an embryo develops as a male or a female, and the genes that are responsible for proper development of the gonads, organs that control an individual's sexual development. It is thought that a genetic chain of events is important for gonadal development, and we aim to find the missing links of that chain and to work out how they fit together, as well as how genetic defects can lead to disorders of sexual development. Defects in sexual development in the human embryo not only result in some of the most common forms of birth defects but also have profound physiological and psychosexual ramifications for the afflicted individuals. A fuller understanding of the causes of these defects will lead to improved patient management.Read moreRead less
Understanding The Role Of PI 3-kinase Mutations In Gastrointestinal Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$283,880.00
Summary
Mutations in the PIK3CA gene are frequently found in bowel cancers but it remains unclear exactly how these mutations are involved in cancer development. We will exploit a unique mouse model to explore the role of PIK3CA mutations in the initiation, progression and-or metastasis of gastrointestinal cancers. This work will provide critical new insights into the biology of PIK3CA mutations and lead to the development of better models for the testing of new anti-cancer therapies.
Validation Of Stat3 As A Therapeutic Target In Diseases Arising From Its Inappropriate Activation By Gp130 Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$674,142.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the exte ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.Read moreRead less
The Intersection Between Hedgehog And Notch Signalling In Medulloblastoma.
Funder
National Health and Medical Research Council
Funding Amount
$620,647.00
Summary
Brain tumours are the second most common malignancy of childhood and the leading cause of cancer related death and disability in children. Medulloblastoma is the most frequent malignant childhood brain tumour, arising in the cerebellum. This application looks at the relationship between two genetic pathways responsible for medulloblastoma which are also drug targets. Understanding this interaction will lead to better treatment options for the disease.
Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy character ....Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy characterized by the presence of seizures during light sleep. In vitro studies using the human mutated DNA (i.e. DNA containing the genetic defect) have suggested that this mutation results in reduced activity of the receptor. Therefore a mouse in which this gene is destroyed would be relevant in understanding the human disease. We have generated an a4 nAChR knockout (KO) mouse and plan to use the mouse to test the idea that loss of function of the a4 nAChR in vivo is associated with enhanced seizure activity. The KO mice do not have unprovoked seizures but appear to have an increased number of major motor seizures in response to pentylenetetrazole, an agent which is known to cause seizures by blocking the effects of the brain inhibitory molecule GABA. Interestingly, a4 nAChRs are known to control the release of GABA. We therefore propose that our knockout mice have seizures because they tend to under produce GABA. We will also make and analyse a mouse line with the same genetic mutation as patients with ADNFLE. The experiments are aimed at understanding the way that seizures are generated and spread in the brain in these rare forms of epilepsy. The hope is that understanding these mechanisms will help us better understand and therefore treat common forms of epilepsy.Read moreRead less
Studies On The Tumour-associated PIK3CA(H1047R) Mutation Using In Vitro And In Vivo Models Of Breast And Ovarian Cancer
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
PIK3CA mutations are frequently found in breast and ovarian cancers but how they cause cancer is not clear. We will exploit a unique mouse model to investigate the functional effects of PIK3CA mutations in cells and their role in cancer development. Understanding the mechanisms by which PIK3CA mutations regulate cell function and drive tumour growth will allow the rationale design of novel anti-cancer agents that specifically target this important cancer pathway.
Identification And Characterisation Of Novel Mouse Models For Recessively Inherited Deafness.
Funder
National Health and Medical Research Council
Funding Amount
$504,750.00
Summary
Hearing loss affects 10% of Australians. Approximately 1 in 1000 children is born deaf. Another 1 in 1000 people develops hearing loss by adulthood. 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. Environmental risk factors include premature birth, infections and exposure to loud n ....Hearing loss affects 10% of Australians. Approximately 1 in 1000 children is born deaf. Another 1 in 1000 people develops hearing loss by adulthood. 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. Environmental risk factors include premature birth, infections and exposure to loud noise. Inherited factors include changes (mutations) in one of many genes whose products are essential for normal hearing. In the majority of children and young people with a hearing impairment the underlying cause is genetic. It is also thought that genetic predisposition frequently contributes to the early onset and the severity of age-related hearing loss. However, it has been difficult to identify the genes causing deafness, and as a consequence we know relatively little about what these genes do. The mouse ear is very similar to the human ear and in this application we propose to use mice to identify and study deafness genes. Australia has a unique resource of mice that are being especially bred to uncover genetic diseases. We have shown that 1 in a 1,000 of these mice have a genetic hearing loss similar to that found in most newborns and young people. These mice therefore provide us with an exceptional opportunity to discover novel deafness genes, which again will provide us with more information about how we hear. We will investigate why changes in these genes causes hearing loss and this information will allow us to determine in detail how genetic and environmental factors lead to hearing loss in young and old. The results will immediately 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