Understanding How Defects In Chromosome Structure Can Cause Disease
Funder
National Health and Medical Research Council
Funding Amount
$546,557.00
Summary
The correct folding of DNA is critical to a cell's survival. This is orchestrated by a special class of proteins called the condensins. Defects in condensin lead to aberrant chromosome folding and disease. We aim to understand how condensin folds chromosomes and why mutations in condensin are increasingly associated with disease.
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
DECIPHERING THE ROLE OF FOXP1 IN MAMMARY STEM CELLS AND DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$569,109.00
Summary
Breast (mammary) epithelial cells undergo major changes across developmental stages, including puberty, pregnancy and lactation. This project will focus on the role of the molecular regulator, Foxp1, and how it influences normal mammary maturation. This work will inform whether Foxp1 is critical for controlling the activation of dormant stem cells and if this pathway can contribute to breast cancer formation when disrupted.
Endocardial sprouting and mechano-signalling in heart trabeculation. This project aims to understand how the ventricles, the pumping chambers of the mammalian heart, form during embryonic life. Critical is the elaboration of trabeculae, myocardial projections that form a sponge-like layer on the inner surface of the chamber wall and which play vital roles in contraction, oxygen and nutrient exchange, conduction and septation. The project expects to develop a deeper understanding of trabeculation ....Endocardial sprouting and mechano-signalling in heart trabeculation. This project aims to understand how the ventricles, the pumping chambers of the mammalian heart, form during embryonic life. Critical is the elaboration of trabeculae, myocardial projections that form a sponge-like layer on the inner surface of the chamber wall and which play vital roles in contraction, oxygen and nutrient exchange, conduction and septation. The project expects to develop a deeper understanding of trabeculation using high resolution, single cell methodologies, and to investigate how bio-mechanical forces from contraction or blood flow influence chambers formation.Read moreRead less
Deciphering The Role Of Scribble In Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$628,789.00
Summary
Scribble is a protein that controls the orientation and organization of all cells within our body. Mutations in the Scribble gene are found in many cancers and also in some patients with spina bifida, however how these mutations cause these diseases is not understood. Here we propose experiments that can be used to link Scribble mutations to specific cellular functions. This information will help us design new therapies to treat diseases driven by tissue disorganization such as cancer.
The Role Of A New Class Of Chromatin Organising Hub
Funder
National Health and Medical Research Council
Funding Amount
$1,145,450.00
Summary
Within the cell nucleus, specific proteins weave DNA into structured loops that are vital for normal cell function. By studying the molecules involved, we have uncovered a ‘dock’ that controls this DNA architecture. We will define the components and function of this ‘dock’, and the resulting rapid cell death that occurs if it is disrupted. We will explore this cell death pathway thoroughly because we think it may help us to develop new cancer therapies.
How The Bcl-2 Protein Family Controls Apoptosis And Impacts On Cancer Development And Therapy
Funder
National Health and Medical Research Council
Funding Amount
$850,346.00
Summary
Impaired cell death (apoptosis) is now recognized as an important step towards cancer and a major barrier to effective therapy. The discoveries on apoptosis by Professor Jerry Adams and colleagues have galvanized the search for drugs that engage the cell’s apoptotic machinery as a new way to treat cancer. His proposed studies aim to clarify how apoptosis is controlled and how the control goes awry in cancer, and to determine how such drugs can be most effectively used to improve cancer treatment ....Impaired cell death (apoptosis) is now recognized as an important step towards cancer and a major barrier to effective therapy. The discoveries on apoptosis by Professor Jerry Adams and colleagues have galvanized the search for drugs that engage the cell’s apoptotic machinery as a new way to treat cancer. His proposed studies aim to clarify how apoptosis is controlled and how the control goes awry in cancer, and to determine how such drugs can be most effectively used to improve cancer treatment.Read moreRead less
A Stem Cell-specific MicroRNA-independent Function Of Drosha
Funder
National Health and Medical Research Council
Funding Amount
$637,702.00
Summary
Stem cells are responsible for producing and replenishing the ~200 specialised cell types in our body. Our goal is to understand the molecular switches that control the function of these cells. We recently discovered that the activity of certain genes within stem cells is controlled by degradation. This degradation is absolutely crucial for safeguarding the function of stem cells. This project will investigate how this novel mechanism is controlled within these cells.
Elucidating The Cellular Processes That Are Critical For P53 Mediated Tumour Suppression
Funder
National Health and Medical Research Council
Funding Amount
$1,016,108.00
Summary
p53 is a tumour suppressor gene that is mutated in ~50% of human cancers. Mutations in p53 cause development of cancer and render malignant cells resistant to chemotherapy. We have identified genes regulated by p53 that appear critical for its tumour suppressive function. In this project, we will use innovative novel genetic tools to discover the cellular and biochemical functions of these genes. The ultimate goal of our studies is to identify novel targets for anti-cancer therapy.
Role Of Bak And Bax Membrane Anchors In Targeting And Apoptotic Pore Formation.
Funder
National Health and Medical Research Council
Funding Amount
$352,319.00
Summary
In cancer cells the normal process of cell death (called apoptosis) is defective, helping abnormal cells to grow and multiply unchecked. The Bak and Bax proteins are members of the Bcl-2 family of apoptosis regulators, and play a pivotal role in mediating cell death. By defining how these proteins form a pore in mitochondria, the point of no return in cell death, will help the development of novel anti-cancer agents that target the Bcl-2 family in general, and Bak and Bax in particular.