Using Mouse Models To Decipher The Function Of Caspase-2 In Limiting Aneuploidy Tolerance And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$871,162.00
Summary
Aneuploidy or abnormal chromosome number is a feature of cancer cells. The extent of aneuploidy is often predictive of prognosis and the effectiveness of cancer treatment. We discovered that a tumour suppressing protein, caspase-2, is important for deleting aneuploid cells that may otherwise become cancerous. In this project we will use cancer models to decipher how caspase-2 safeguards against aneuploidy and cancer to better understand how cancer cells can survive and be targeted for treatment.
Spatial Arrangement And Three-dimensional Structure Of Human Centromeres
Funder
National Health and Medical Research Council
Funding Amount
$283,000.00
Summary
Centromeres occur at the main constriction of chromosomes. They allow duplicated chromosomes to divide, control cell division and are involved in the control of gene expression. Faulty centromeres are found in many types of cancer and in other genetic diseases. They are also implicated in extra-chromosome disorders such as Down syndrome. Centromeres have a different structure to the rest of the chromosome and it is this structure we wish to study. We want to see how centromere DNA folds up tight ....Centromeres occur at the main constriction of chromosomes. They allow duplicated chromosomes to divide, control cell division and are involved in the control of gene expression. Faulty centromeres are found in many types of cancer and in other genetic diseases. They are also implicated in extra-chromosome disorders such as Down syndrome. Centromeres have a different structure to the rest of the chromosome and it is this structure we wish to study. We want to see how centromere DNA folds up tightly at the centromere. We also want to find out why centromeres locate in certain regions of the nucleus, because this may influence how the centromere works and how they regulate genes. Human centromeres come in many sizes and forms; by looking at a wide range of human centromeres, common structural and spatial properties will emerge. We have discovered very small centromeres - neocentromeres - which are much easier to study than other centromeres. We have used these centromeres to construct human minichromosomes, which we believe represent the main, all-human way forward to treat people with gene therapy. One way to help us achieve our aims is to stretch out centromeres in a controlled way to make it easier to visualise their structure. Our tools will be antibodies, fluorescently-labelled proteins and high resolution microscopes. These include an electron microscope, and microscopes that can produce optical sections and in turn a 3D image. One of these is the confocal laser scanning microscope; the other involves removal of out-of-focus light from images using deconvolution software to achieve the same goal. We will detect different centromere proteins with different fluorochromes for fluorescence microscopes and different sizes of gold particles for the electron microscope. Using these microscopes we have already been able to find out where one of our neocentromeres is located within the nucleus. We have also started to look at centromeres with the electron microscope.Read moreRead less
Role Of DNA Methylation And Non-coding RNA In Human Centromere Function
Funder
National Health and Medical Research Council
Funding Amount
$499,000.00
Summary
A chromosome is a grouping of coiled strands of DNA, containing many genes. Every human cell has 23 pairs of chromosomes, which together comprise the genome. Both gain and loss of any of these chromosomes will lead to severe medical problems including birth defects and cancer development. Thus, the understanding of the mechanisms underlying the exact passage of these chromosomes from a parental cell to two new cells during cell division, and how the information is copied from from one cell gener ....A chromosome is a grouping of coiled strands of DNA, containing many genes. Every human cell has 23 pairs of chromosomes, which together comprise the genome. Both gain and loss of any of these chromosomes will lead to severe medical problems including birth defects and cancer development. Thus, the understanding of the mechanisms underlying the exact passage of these chromosomes from a parental cell to two new cells during cell division, and how the information is copied from from one cell generation to another, is an important area of research, however, much remains to be learnt about the mechanisms. Our laboratory was the first to discover a key component of the chromosome that is involved in the regulation of the cell division process, ensuring the accurate segregation of chromosomes. This structure, known as a neocentromere, is an ideal model system to study important aspects of chromosome segregation. The present project proposes to study the properties of this neocentromere in detail. The outcome will contribute to our knowledge on the processes underlying cell and chromosome division, which will ultimately have a direct impact on our understanding of the causes for some of the most common clinical conditions that affect human health.Read moreRead less