The Role Of Heterochromatin In Regulating Cellular Proliferation And Development
Funder
National Health and Medical Research Council
Funding Amount
$504,000.00
Summary
Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the ....Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein (histones) to form a structure known as chromatin. It has become clear that the chromatin structure encompassing a gene is the critical factor that determines whether a gene is expressed or silenced. We propose that developmental and cell-type specific mechanisms operate in a cell to assemble genes into highly specialised chromatin structures that permit (euchromatin) or restrict (heterochromatin) gene expression. In other words, the genome of each different cell type is organised into a unique and dynamic chromatin pattern and this pattern determines the gene expression profile. This investigation will show that the critical cellular mechanism that determines the chromatin pattern for a particular cell type is the regulation of the quantity and quality of heterochromatin. Specifically, we will demonstrate that this is achieved, in a developmental and tissue specific manner, by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . In addition, we will expose a new mechanism of how heterochromatin formation controls the rate of cellular proliferation. This information will provide new insights into how gene expression profiles are established at precise times in early development, and offer a new strategy to inhibit the proliferation of cancer cells.Read moreRead less
The Function Of An Essential Histone Variant During Early Development.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is capable of blocking gene expression therefore one important function of chromati ....Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is capable of blocking gene expression therefore one important function of chromatin is to prevent unwanted gene expression which is essential to allow an organism to develop properly. When gene expression is not accurately controlled by chromatin developmental defects or cancer could result from the production of incorrect proteins. To control correct gene expression, highly specific mechanisms must operate in the cell to remove, or disrupt, nucleosomes at certain genes at a precise time during development. One mechanism that we believe to be important is changing the make-up of a nucleosome. This can be achieved in the cell by the replacement of histones with different specialised forms of these histones (variants). It is thought that these histone variants could specifically expose certain genes and thereby turn them on. Once the correct protein is made in sufficient amounts the histone variants could be rapidly exchanged for the normal histones to shut off the gene. Employing a new approach, we will study one of these histone variants to discover the role it plays in turning genes on at precise times in early development during the formation of different specialised cell types. This new information may define targets for the prevention of incorrect gene expression during cancer progression or abnormal development.Read moreRead less
Multipotent Stem Cells Derived From Postimplantation Mouse Embryos: Evaluation Of Germ Layer Differentiation Potential
Funder
National Health and Medical Research Council
Funding Amount
$788,818.00
Summary
This study of the properties of cells that can differentiate into specific lineages provides useful insights into the cellular and molecular mechanisms for the specification of these progenitors from the pluripotent stem cells. The procurement of tissue-specific precursor cells that are capable of self-renewing and population expansion is a critical pre-requisite for achieving directed differentiation of stem cells into therapeutically useful cells for tissue replacement and regeneration.
This project aims to investigate novel ways to treat children with the inherited brain disorder known as MPS IIIA. This condition is currently untreatable and children generally die in their teens. We will use a mouse model of this condition to examine the effectiveness of combining two different treatment approaches, in order to maximise outcomes.
Liver Cell Transplantation For The Treatment Of Liver Based Metabolic Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$444,143.00
Summary
We propose to investigate the role of liver cell transplantation (LCT) for the therapy of inherited liver-based metabolic diseases using a methylmalonic aciduria (MMA) mouse model. LCT provides an exciting alternative to whole organ transplantation. Initially it was considered liver cells would be immunopriviledged. This has not proven to be the case. Immune modulation will be important. We will also examine immune modulation using antibodies to optimise longterm survival of allogeneic cells.
A Pragmatic Randomised Clinical Trial Of Nicotine Vaporisers Added To Smoking Cessation Treatment For Priority Populations Living With Comorbidities
Funder
National Health and Medical Research Council
Funding Amount
$1,499,145.00
Summary
Smoking is a leading cause of early death for people with certain health conditions because they are more likely to smoke and are also at greater risk of tobacco-related disease. This clinical trial will test whether encouraging people living with Hepatitis C Virus, people on opiate substitution therapy and people living with HIV who smoke to use nicotine vaporisers long-term, in addition to current smoking cessation treatments, will help them to stay abstinent from smoking.
Developing Exon Replacement Gene Therapy To Cure Rett Syndrome: An Innovative Model For Neurodevelopmental Disorders
Funder
National Health and Medical Research Council
Funding Amount
$475,105.00
Summary
There is no cure for neurodevelopmental disorders such as Rett syndrome which is caused by mutations in the MECP2 gene. Gene therapy is ineffective due to the 'Goldilocks' effect where too little, as well as too much expression of MECP2 causes disease. Here a gene editing therapy will be tested in patient cells and mouse model that will maintain the normal cellular expression of MECP2 by cutting out the mutated regions of the gene (exons) and replacing them with repaired copies.
The Developmental Hierarchy Of Haemopoietic Lineage Relationships
Funder
National Health and Medical Research Council
Funding Amount
$192,000.00
Summary
The blood cells are all the progeny of a very rare stem cell, that is thought to reside in the bone marrow. The stem cell maintains itself throughout the life span of the individual as well as generating the billions of more mature cell types required in the blood. However the processes and stages that immature cells pass through from the stem cell to ultimately a mature functional blood cell such as a lymphocyte remain disputed. This study aims to determine to relationship of the various blood ....The blood cells are all the progeny of a very rare stem cell, that is thought to reside in the bone marrow. The stem cell maintains itself throughout the life span of the individual as well as generating the billions of more mature cell types required in the blood. However the processes and stages that immature cells pass through from the stem cell to ultimately a mature functional blood cell such as a lymphocyte remain disputed. This study aims to determine to relationship of the various blood cell progeny with each other and thus to provide a lineage map of the system. To do this we will isolate precursors at various stages along the developmental pathways and determine their capabilities to produce the normal range of progeny. We will then use a number of genetically altered mouse strains to assess the genes involved in this process. These studies will help provide an underlying scientific basis to the attempts to development a number of stem cell therapies that are aimed at boosting or directing stem cell production in procedures such as bone marrow transplantation for leukemia and immune deficiency. In addition a number of characterized human blood malignancies seem to have developed along aberrant pathways indicating that inappropriate lineage specification may be a factor in cancer.Read moreRead less
Adult Stem Cell Transplantation Therapy In Parkinsonian Rat
Funder
National Health and Medical Research Council
Funding Amount
$526,517.00
Summary
Parkinson's disease is a progressive neurodegenerative disorder characterised by slowness of movement, muscle rigidity and tremor. It affects about 1% of the population at age 50 and 10% over age 80. Symptoms are caused by low levels of dopamine, a chemical in the brain that helps control movement. The symptoms increase in severity with time, leading to increasing difficulty in walking, speaking, writing, swallowing and sleeping and increasing the incidence of broken bones from falls. Parkinson' ....Parkinson's disease is a progressive neurodegenerative disorder characterised by slowness of movement, muscle rigidity and tremor. It affects about 1% of the population at age 50 and 10% over age 80. Symptoms are caused by low levels of dopamine, a chemical in the brain that helps control movement. The symptoms increase in severity with time, leading to increasing difficulty in walking, speaking, writing, swallowing and sleeping and increasing the incidence of broken bones from falls. Parkinson's disease is incurable but the symptoms can be controlled with medications that replace the lost dopamine. Medications become less effective as the disease progresses and there is need for new therapies. Worldwide the hunt is on to discover new cell transplantation therapies to replace the dopamine in the brain and to prevent degeneration of the still surviving dopamine cells. Although embryonic stem cells might be useful for such therapies, they raise the risk of tumour formation from the transplanted cells. This aim of this proposal is to test, in parkinsonian rat, a therapy in which adult stem cells from the patient are transplanted into their own brain to provide a new source of dopamine. We have discovered a new and unique source of adult stem cells, the sense organ of smell in the nose. Small samples can be taken through the nose and we can grow these adult stem cells from people of all ages, including people with Parkinson's disease. As adult stem cells they avoid the ethical issues associated with embryonic stem cell transplantation and as cells from the same patient, they are not rejected by the immune system. This is being tested in principle by a world-first clinical trial in which we are taking another cell type from the nose, growing it in the lab, and transplanting into the injured spinal cord in a search for a cure for paraplegia. This project takes the first steps to developing a new treatment for Parkinson's disease using a patient's own adult stem cells.Read moreRead less
Prevention And Treatment Of Bone Infection With CSA-90
Funder
National Health and Medical Research Council
Funding Amount
$350,983.00
Summary
Bone infections are a major challenge to treat, especially with the rise of drug resistant “superbugs”. We have access to a new agent, CSA-90, that has dual properties of being anti-microbial (antibiotic) and helps encourage bone growth. This project aims to expand upon our prior research and test CSA-90 for the treatment of chronic bone infections. We will also look at applying this technology to joint replacements and this drug may be particularly useful for coating orthopaedic implants.