I am a molecular biologist determining the function of extracellular matrix proteins critical for development, function and repair of important tissues such as arteries, lung, kidney, eye and bone.
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
Transcriptional Regulation Of The Complement Receptor 2 Gene (CR2/CD21) During B Cell Lineage Committment
Funder
National Health and Medical Research Council
Funding Amount
$466,500.00
Summary
The complement system is a very important pathway within the human immune system. One of the receptors within this system is complement receptor 2 or CR2. CR2 has not only been shown to be important within the inflammatory response and defence against microbes but is also important in normal generation of a B cell immune response . B cells not only produce antibodies against foreign organisms but in some cases dysfunction of the B cell can bring about autoimmunity by production of antibodies aga ....The complement system is a very important pathway within the human immune system. One of the receptors within this system is complement receptor 2 or CR2. CR2 has not only been shown to be important within the inflammatory response and defence against microbes but is also important in normal generation of a B cell immune response . B cells not only produce antibodies against foreign organisms but in some cases dysfunction of the B cell can bring about autoimmunity by production of antibodies against self tissues and cells . How the CR2 gene turns on expression on different cells within the immune system is complex. The amount of receptor on the surface of antibody producing B cells has important implications to B cell biology. As CR2 expression is turned on at an important point within the antibody producing B cell and the levels of this receptor can influence B cell function, understanding how this gene is regulated is important.Read moreRead less
TRANSCRIPTIONAL AND FUNCTIONAL CONSEQUENCES OF STAT3 ACTIVATION IN THE HEART
Funder
National Health and Medical Research Council
Funding Amount
$413,694.00
Summary
Recent statistics show that the disease known commonly as heart failure accounts for about 3000 deaths each year in Australia. Worldwide, a staggering 10 million people are thought to currently suffer from heart failure, with this number continuing to rise despite decreasing numbers of people suffering from other forms of heart and blood vessel disease. What causes a healthy heart to fail remains unclear, although in some circumstances failure is known to be initiated by genetic factors, viral f ....Recent statistics show that the disease known commonly as heart failure accounts for about 3000 deaths each year in Australia. Worldwide, a staggering 10 million people are thought to currently suffer from heart failure, with this number continuing to rise despite decreasing numbers of people suffering from other forms of heart and blood vessel disease. What causes a healthy heart to fail remains unclear, although in some circumstances failure is known to be initiated by genetic factors, viral factors, alcoholism, high blood pressure, or when the heart is damaged in a heart attack. We are interested in the molecular mechanisms that underlie the progression of the normal heart to failure. In 2003 we reported on altered signalling pathways in the failing human heart, and noted the increased phosphorylation of a spliceform of the transcription factor STAT3 in patients with heart failure. In this project, we will evaluate a larger group of heart failure patients for changes in phosphorylation of their STAT3 proteins. We will also increase the expression of an activated form of the STAT3 proteins in rat heart cells, and check whether there are accompanying changes in gene expression profiles that indicate a potential role in heart failure, or whether these cells are now predisposed to die. This will be extended with the use of transgenic animals (mice) engineered to overexpress activated STAT3 proteins. Again, we will focus on gene expression profiles. We will also evaluate whether the hearts of these animals are more likely to fail, either as the animals age, or when external stresses are experienced. With this information, we will be able to state whether STAT3 is a contributor to heart failure, and therefore whether it is an attractive target for future therapies aimed at reducing the morbidity and mortality of heart failure worldwide.Read moreRead less
Fibrtic lung diseases are a major health burden, and are a leading causes of mortality and morbidity worldwide. These diseases are effectively incurable, and a considerable number eventually require lung transplants. As such these diseases are prime candidates for stem cell therapies to regenerate and repair the lung. However, the lack of knowledge about the precise identity, organisation and regulation of these cells; how to deliver them effectively to the damaged lung; and how to pre-condition ....Fibrtic lung diseases are a major health burden, and are a leading causes of mortality and morbidity worldwide. These diseases are effectively incurable, and a considerable number eventually require lung transplants. As such these diseases are prime candidates for stem cell therapies to regenerate and repair the lung. However, the lack of knowledge about the precise identity, organisation and regulation of these cells; how to deliver them effectively to the damaged lung; and how to pre-condition their site of lodgement to best harness their potential. This project aims to address these issues. We have recently identified a rare population of cells in the adult mouse lung which has a number of characteristics consistent with that of an adult stem cell. We are able to grow these cells in tissue culture, and we have preliminary data suggesting that they can regenerate lung tissue when transplanted. The aim of this project is to precisely identify these cells, develop methods for their isolation and determine their location in the lung. The assays we will develop in this model will then be used to identify stem cells in the bone marrow which have similar properties and which could potentially be used clinically to alleviate lung disease. The project brings together a group of investigators with unique expertise in the isolation and analysis of adult stem cells, and in clinical and experimental respiratory medicine to develop preclinical models in the mouse which are prerequisite for the developement and implementation of step cell based therapies for lung disease in humans.Read moreRead less
Tuning mesenchymal stem cell lifespan, performance, and differentiation. This project aims to fully characterise a unique molecular process that strongly modulates mesenchymal stem cell lifespan and behaviour. This work is significant, as it is expected to reveal new concepts underpinning the mechanistic actions of classical structural proteins. It will also shape a more nuanced understanding of the context-dependent mechanical and biochemical signals that regulate stem cell fate and function. E ....Tuning mesenchymal stem cell lifespan, performance, and differentiation. This project aims to fully characterise a unique molecular process that strongly modulates mesenchymal stem cell lifespan and behaviour. This work is significant, as it is expected to reveal new concepts underpinning the mechanistic actions of classical structural proteins. It will also shape a more nuanced understanding of the context-dependent mechanical and biochemical signals that regulate stem cell fate and function. Expected outcomes include new knowledge surrounding native extracellular matrix and stem cell biology, and the development of strategies to define and tailor stem cell properties. This work is anticipated to drive new technologies that can efficiently and robustly manipulate stem cells for diverse functional applications.Read moreRead less
Metabolic control of organ growth and regeneration. One of the fundamental questions in biology is to understand how organ size is regulated at the cellular and organismal level. The Hippo/Yap pathway plays a central role in the regulation of organ size and it is impacted by environmental cues including nutrient status. This research proposal aims to use zebrafish to elucidate the role that the Hippo/Yap pathway plays in reprogramming lipid metabolism to fuel tissue growth in development and reg ....Metabolic control of organ growth and regeneration. One of the fundamental questions in biology is to understand how organ size is regulated at the cellular and organismal level. The Hippo/Yap pathway plays a central role in the regulation of organ size and it is impacted by environmental cues including nutrient status. This research proposal aims to use zebrafish to elucidate the role that the Hippo/Yap pathway plays in reprogramming lipid metabolism to fuel tissue growth in development and regeneration. Ultimately, this work aims to identify metabolic dependencies required for organ growth and regeneration. Expected outcomes include scholarly publications revealing fundamental principles underlying tissue growth, new resources for the research community and training for research students.Read moreRead less
Adaptive reprogramming of metabolism in regeneration. . Biologists have long been intrigued at the phenomenon of organ regeneration. Unlike most human organs, the liver exhibits the remarkable capacity to regenerate. Despite decades of research, the molecular underpinnings of liver regeneration are poorly understood. This research proposal aims to use zebrafish to elucidate the pathways involved in sensing injury and activating an adaptive transcriptional and metabolic response to orchestrate re ....Adaptive reprogramming of metabolism in regeneration. . Biologists have long been intrigued at the phenomenon of organ regeneration. Unlike most human organs, the liver exhibits the remarkable capacity to regenerate. Despite decades of research, the molecular underpinnings of liver regeneration are poorly understood. This research proposal aims to use zebrafish to elucidate the pathways involved in sensing injury and activating an adaptive transcriptional and metabolic response to orchestrate regeneration. Ultimately, this works aims to understand the metabolic requirements for regeneration. Expected outcomes include scholarly publications revealing fundamental principles of regeneration, new resources and pipelines for the research community as well as training for research students.Read moreRead less