Generation Of Mouse Models To Study The Roles Of Different Bcl-2 Family Members In The Regulation Of Apaptosis
Funder
National Health and Medical Research Council
Funding Amount
$420,872.00
Summary
Programmed cell death, or apoptosis, is required for the removal of infected, damaged or unwanted cells and its disrupted regulation is implicated in cancer, autoimmunity and degenerative disorders. The Bcl-2 family of proteins are key regulators of apoptosis. We propose to generate several mouse models to better understand the relationships between the different members of the Bcl-2 family in an effort to control this pathway for therapeutic purposes.
The Role Of The Gtf2i Gene Family In Behaviour And Williams Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$629,396.00
Summary
Williams Syndrome (WS) is a complex neurodevelopmental disorder in humans caused by a deletion of 21 genes on chromosome 7. This results in a reduced IQ and marked visuospatial deficiencies. However, unlike other forms of mental retardation, some important cognitive abilities are completely normal. WS patients show normal development of linguistic abilities and anecdotal evidence suggests they possess an above average musical ability. In addition, these individuals also possess a characteristic ....Williams Syndrome (WS) is a complex neurodevelopmental disorder in humans caused by a deletion of 21 genes on chromosome 7. This results in a reduced IQ and marked visuospatial deficiencies. However, unlike other forms of mental retardation, some important cognitive abilities are completely normal. WS patients show normal development of linguistic abilities and anecdotal evidence suggests they possess an above average musical ability. In addition, these individuals also possess a characteristic overfriendly, gregarious personality with little inhibition towards strangers. Such a characteristic cognitive and behavioral profile in a genetic disorder has provided convincing evidence that genes play a role in specifying cognitive abilities and behavior. This interesting syndrome gives us an insight into the perplexing debate of Nature vs Nurture. It also provides a unique and invaluable opportunity to dissect the role of certain genes in complex neurodevelopmental pathways that result in cognition and behavior. Recently, patients with smaller (atypical) deletions of genes in the WS region have been described. These patients do not display the full 'classical' range of WS characteristics. The identification of which genes are deleted in these patients suggests that two genes in particular, GTF2IRD1 and GTF2I, are involved in visuospatial abilities, sociability and specific anxieties and phobias. Our laboratory was the first to identify proteins encoded by GTF2IRD1, known as MusTRDs, that act for the most part to suppress gene expression. Furthermore, our laboratory has been studying a mouse model in which the Gtf2ird1 gene has been deleted, similar to the situation in WS, and have found that the mice are more 'social' and exploratory. In this project, we want to determine if other behavioural features of WS are contributed to by this gene and-or its related gene, Gtf2i, and to characterize the role that these genes play in neuronal cell function.Read moreRead less
The Role Of Centromere Proteins In Centromere Assembly, Chromosome Instability, And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$687,750.00
Summary
Our genetic information are organised into compact structures known as chromosomes in our cells. Each human cell has 46 chromosomes. Excess or insufficient copies of these chromosomes will cause genetic imbalance that often results in serious clinical problems such as Down syndrome, cancer, embryonic death, and a host of other syndromes. The study of the process of how the exact number of chromosomes is distributed amongst daughter cells when cells divide is therefore an important area of resear ....Our genetic information are organised into compact structures known as chromosomes in our cells. Each human cell has 46 chromosomes. Excess or insufficient copies of these chromosomes will cause genetic imbalance that often results in serious clinical problems such as Down syndrome, cancer, embryonic death, and a host of other syndromes. The study of the process of how the exact number of chromosomes is distributed amongst daughter cells when cells divide is therefore an important area of research. Our laboratory has focused research on a key structure of the chromosome known as the centromere that determines how this process is controlled. The present project aims to study the properties of the centromere in detail using the technique of targeted gene mutation in mice. In these mice, the functions of individual genes that make specific centromere proteins are destroyed or modified through a precisely controlled mutation process. The effects such mutations have on the development of the animals and on chromosome division can then be analysed in great detail. The outcome will be a significant increase in our understanding of the functions of the different centromere proteins, an understanding that is key to the further advancement of our knowledge on the aetiology of some of the most frequently seen disease conditions in humans, including cancer.Read moreRead less
Using The A33 Antigen Gene Locus To Generate Novel Mouse Models Of Colon Cancer
Funder
National Health and Medical Research Council
Funding Amount
$376,320.00
Summary
Colorectal (or bowel) cancer is a major health problem in Australia. It is the most common cancer reported to Australian cancer registries and was responsible for 14% of cancer deaths in 1990, the latest year for which national figures are available. Only lung cancer, which caused 20% of cancer deaths was a more common cause of cancer death. Approximately 1 in 21 Australians will develop colorectal cancer during his-her lifetime. The risk of colorectal cancer increases with age, with risk rising ....Colorectal (or bowel) cancer is a major health problem in Australia. It is the most common cancer reported to Australian cancer registries and was responsible for 14% of cancer deaths in 1990, the latest year for which national figures are available. Only lung cancer, which caused 20% of cancer deaths was a more common cause of cancer death. Approximately 1 in 21 Australians will develop colorectal cancer during his-her lifetime. The risk of colorectal cancer increases with age, with risk rising progressively and sharply from age 50 onwards. Like all cancers, colorectal cancer results from the progressive acquisition of mutations in genes that normally ensure a balance between cell growth and cell death. Mutations which predispose individuals to colorectal cancer accumulate in the epithelial cells that provide the lining to the bowel. The progression of colorectal cancer proceeds through a number of distinct anatomical stages which can be easily recognised by pathologists. Mutations in a number of genes (known as APC, beta-catenin, Kirsten-ras, p53, SMAD2, SMAD4) are commonly found in colorectal tumours. Moreover, some of the mutations are highly associated with distinct stages of colon tumour development. As yet, however, we have no real insights into how these mutations cooperate with each other to produce full-blown (malignant) colorectal cancer. In our proposal, we are aiming to establish colorectal cancer in mice. Our approach will be to progressively introduce mutant genes into intestinal epithelial cells (singly and in combination) and study how they cooperate with each other to produce benign, and ultimately, malignant tumours in the intestines of mice. This will help us to understand which mutant genes are required for each stage in tumour development and may provide more rational approaches to bowel cancer screening and treatment.Read moreRead less
A Transgenic Analysis Of The Physiologic Roles Of Signalling Domains In The Growth Hormone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$262,500.00
Summary
The key hormone promoting growth postnatally is growth hormone (GH), and it acts through the growth hormone receptor to initiate a variety of signals which regulate gene expression. In addition to its role in growth, GH is an importnat metabolic regulator in starvation. It also appears to play a significant role in the ageing process, since mice lacking the GH receptor live 50% longer than normal mice. Although the signalling systems used by the GH receptor are reasonably well defined in vitro, ....The key hormone promoting growth postnatally is growth hormone (GH), and it acts through the growth hormone receptor to initiate a variety of signals which regulate gene expression. In addition to its role in growth, GH is an importnat metabolic regulator in starvation. It also appears to play a significant role in the ageing process, since mice lacking the GH receptor live 50% longer than normal mice. Although the signalling systems used by the GH receptor are reasonably well defined in vitro, we have no idea which signals are used to control postnatal growth, metabolism and ageing in the live animal. With NHMRC support, we have been creating mice with individual signalling domains of the GH receptor deleted. This proposal aims to use these mice to determine how the GH receptor brings about its actions of promoting postnatal growth, regulating metabolism and altering lifespan. In particular, through the use of gene arrays, we intend to define the key genes regulated in these processes. This would provide potential therapeutic targets for drug development to individually alter these key processes.Read moreRead less
The Characterisation Of The Glycolytic Pathway And TCA Cycle On First And Second Phase Insulin Secretion
Funder
National Health and Medical Research Council
Funding Amount
$85,716.00
Summary
In normal individuals, special cells in the pancreas - beta cells - secrete insulin. Insulin controls blood glucose. However, in diabetes, these beta cells have failed and are unable to perform their function, possibly due to faulty energy production. This project examines the underlying biochemical processes, in particular the energy requirements for insulin secretion. If we can repair this fault, it could identify novel targets for the treatment of diabetes.