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
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
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.
Regulation of DNA replication initiation during Drosophila development. This proposal addresses the fundamental issue of the regulation of DNA
replication during development, using the animal model system, Drosophila melanogaster. This research uses a whole animal genetic and cell biological approach to explore DNA replication regulatory mechanisms that are present in multicellular organisms but not in yeast. The work undertaken here will make a significant contribution to our understanding of ....Regulation of DNA replication initiation during Drosophila development. This proposal addresses the fundamental issue of the regulation of DNA
replication during development, using the animal model system, Drosophila melanogaster. This research uses a whole animal genetic and cell biological approach to explore DNA replication regulatory mechanisms that are present in multicellular organisms but not in yeast. The work undertaken here will make a significant contribution to our understanding of DNA replication regulation within a developing organism that will be relevant to all animals.Read moreRead less
Unveiling and characterisation of a fundamental pathway important in cell division. This work will have a major impact by producing top quality research that addresses a fundamental biological question of relevance to all organisms. The research will advance understanding of genetic factors important in foetal and early childhood development and proliferative disorders that occur during ageing. This work will provide intellectual and practical training to Honours and PhD students and postdoctora ....Unveiling and characterisation of a fundamental pathway important in cell division. This work will have a major impact by producing top quality research that addresses a fundamental biological question of relevance to all organisms. The research will advance understanding of genetic factors important in foetal and early childhood development and proliferative disorders that occur during ageing. This work will provide intellectual and practical training to Honours and PhD students and postdoctoral researchers in the disciplines of Molecular Genetics, Molecular & Cellular Biology, Developmental Cell Biology, Mass Spectrometry and Proteomics, which will be of immense benefit to their scientific careers and the Australian scientific community.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