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
Capturing tissue-specific progenitors from embryos and stem cells. This project aims to delineate the precursor cells in the embryo that give rise specifically to major cell types in the body. The project will use genetic analysis to elucidate the critical genetic activity that underpins the genesis of these precursor cells and to track the trajectory and the scope of cell differentiation. The embryological knowledge will provide insights into the fundamentals of developmental process for gener ....Capturing tissue-specific progenitors from embryos and stem cells. This project aims to delineate the precursor cells in the embryo that give rise specifically to major cell types in the body. The project will use genetic analysis to elucidate the critical genetic activity that underpins the genesis of these precursor cells and to track the trajectory and the scope of cell differentiation. The embryological knowledge will provide insights into the fundamentals of developmental process for generating cellular diversity and enable identifying unique precursors and the evaluation of the efficacy of deriving the biological relevant cell types from the stem cells. This project expects to have a significant impact on the translation to cell production methodology for tissue engineering and bioreactor technology.Read moreRead less
Australian Laureate Fellowships - Grant ID: FL180100019
Funder
Australian Research Council
Funding Amount
$2,906,976.00
Summary
An in situ structural study of Drosophila embryonic patterning. This project aims to develop and deploy an in situ structural biology approach, which enables direct visualisation of large macromolecular structures in cells, to be used in combination with molecular genetics, proteomics and computational biology. In situ structural biology has the potential to revolutionise discovery across life science, providing direct insight into macromolecular structure and function. This project will establi ....An in situ structural study of Drosophila embryonic patterning. This project aims to develop and deploy an in situ structural biology approach, which enables direct visualisation of large macromolecular structures in cells, to be used in combination with molecular genetics, proteomics and computational biology. In situ structural biology has the potential to revolutionise discovery across life science, providing direct insight into macromolecular structure and function. This project will establish the field of in situ structural biology in Australia by studying how a model organism, the fruit fly Drosophila melanogaster controls the development of how the head and tail of the embryo are specified. The project will further develop new instrumentation and approaches that will bring in situ biology to the wider scientific community.Read moreRead less
Programmed cell death (PCD), also known as apoptosis, plays a fundamental role in cell and tissue homeostasis and its misregulation is implicated in many human diseases. Many hormones control PCD but their mechanisms of action remain poorly understood. As hormones, in particular the steroid hormones, are directly linked to the pathogenesis of many forms of cancer, including breast, prostate and ovarian cancer, some of the most common malignancies afflicting the society, it is important to study ....Programmed cell death (PCD), also known as apoptosis, plays a fundamental role in cell and tissue homeostasis and its misregulation is implicated in many human diseases. Many hormones control PCD but their mechanisms of action remain poorly understood. As hormones, in particular the steroid hormones, are directly linked to the pathogenesis of many forms of cancer, including breast, prostate and ovarian cancer, some of the most common malignancies afflicting the society, it is important to study the mechanism of hormonal control of apoptosis in order to identify components of the regulatory apparatus. Identification of precise factors that regulate PCD will not only provide basic understanding of hormone-controlled PCD, but any novel factors involved in the control of cellular levels of death activators or death inhibitors are potential targets for anticancer drug development. This proposal is based on our ongoing studies, which combine the powerful biochemical and cellular approaches with the in vivo studies in vinegar fly (Drosophila) to address complex issues that are often difficult to pursue by the direct use of mammalian systems. We believe that the results from this study will provide novel insights into the mechanisms of hormone-regulated control of PCD and how these control mechanisms are disrupted under pathological conditions.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE120101242
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Regulation of germ cell number and quality by Fizzy-related protein. Females have a limited supply of eggs in their ovaries and it appears that the Fizzy-related gene (FZR1) is important in making sure this full complement is gained. By using novel mouse knockouts of the FZR1 gene, the project will determine how this protein functions at the earliest stages of egg development.
Awaking quiescent neural stem cells. This project aims to generate new knowledge in the area of the evolutionary size of animals and plants, which is determined by intrinsic cell regulation and is constrained by nutrient availability. Brain size is perhaps the most profound example of this. Brain size regulation is underpinned by control of proliferation of neural stem cells (NSCs). Using Drosophila NSCs, the project will examine how nutrients impact on NSC quiescence versus activation, a key ch ....Awaking quiescent neural stem cells. This project aims to generate new knowledge in the area of the evolutionary size of animals and plants, which is determined by intrinsic cell regulation and is constrained by nutrient availability. Brain size is perhaps the most profound example of this. Brain size regulation is underpinned by control of proliferation of neural stem cells (NSCs). Using Drosophila NSCs, the project will examine how nutrients impact on NSC quiescence versus activation, a key characteristic of stem cell control throughout evolution. This will increase our understanding of how energy metabolism and nutrition influence organ size control in multicellular organisms, by determining how organs communicate with each other to convert nutrient signals to action stem cell proliferation.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE170100167
Funder
Australian Research Council
Funding Amount
$372,000.00
Summary
Molecular signals guiding dynamic cell movement during blood vessel growth. This project aims to discover how cells interact within the developing blood vessel sprout. Blood vessels form complex branched networks composed of arteries, capillaries and veins that supply oxygen and nutrients to all body tissues. The development and maintenance of blood vessels depends on the coordination of movement and adhesion between individual endothelial cells in the vessel wall, but the signals controlling th ....Molecular signals guiding dynamic cell movement during blood vessel growth. This project aims to discover how cells interact within the developing blood vessel sprout. Blood vessels form complex branched networks composed of arteries, capillaries and veins that supply oxygen and nutrients to all body tissues. The development and maintenance of blood vessels depends on the coordination of movement and adhesion between individual endothelial cells in the vessel wall, but the signals controlling these actions are unknown. This project aims to reveal how the vascular tree forms during development, which is expected to improve the engineering of functional, vascularised organs in the biotech sector.Read moreRead less
Control of developmental switches by importin 5. Aims: This project will study a key molecular switch called IPO5, a protein that is required for cells and organs to form and function normally, and it will reveal how it works.
Significance: These experiments will provide the first complete description of how this molecular switch controls the behaviour of a cell across its lifespan. IPO5 is highly conserved, so these studies will be relevant to a wide range of animals.
Expected Outcomes: This k ....Control of developmental switches by importin 5. Aims: This project will study a key molecular switch called IPO5, a protein that is required for cells and organs to form and function normally, and it will reveal how it works.
Significance: These experiments will provide the first complete description of how this molecular switch controls the behaviour of a cell across its lifespan. IPO5 is highly conserved, so these studies will be relevant to a wide range of animals.
Expected Outcomes: This knowledge will reveal how IPO5 controls formation of sperm by revealing what other proteins it binds to and how this affects cell signaling and responses to the environment.
Benefits: This will provide information about potential interventions to control fertility or to repair abnormal cells.
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Revealing the mechanobiology of neural tube formation. This project aims to understand the formation of the neural tube; a fundamental tissue structure that generates the brain and the spinal cord. Using interdisciplinary approaches and exploiting recent advances in transgenic and imaging technologies, we expect to reveal the complex interplay between cells and their environment that generates mechanical forces to direct neural tissue formation. Outcomes include knowledge of previously intractab ....Revealing the mechanobiology of neural tube formation. This project aims to understand the formation of the neural tube; a fundamental tissue structure that generates the brain and the spinal cord. Using interdisciplinary approaches and exploiting recent advances in transgenic and imaging technologies, we expect to reveal the complex interplay between cells and their environment that generates mechanical forces to direct neural tissue formation. Outcomes include knowledge of previously intractable developmental processes, training of future scientists and development of international collaborations. This should provide enhanced imaging capacity, a higher quality scientific workforce and position Australia at the forefront of cell and developmental biology.Read moreRead less