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
The balance between cell division and programmed cell death is crucial for normal development, maintenance of homeostasis, and immune system function. Inappropriately regulated cell death contributes to the pathogenesis of a wide variety of human diseases including neurodegenerative disorders, autoimmune syndromes and several forms of cancer. Death receptors such as Fas and TNFR1 are cell-surface sensors that trigger cellular destruction by apoptosis in response to specific extracellular death s ....The balance between cell division and programmed cell death is crucial for normal development, maintenance of homeostasis, and immune system function. Inappropriately regulated cell death contributes to the pathogenesis of a wide variety of human diseases including neurodegenerative disorders, autoimmune syndromes and several forms of cancer. Death receptors such as Fas and TNFR1 are cell-surface sensors that trigger cellular destruction by apoptosis in response to specific extracellular death signals. Recent studies have demonstrated that the mechanisms of signal transduction through Fas and TNFR1 differ significantly, however, they both require the adaptor protein FADD to induce apoptosis. In this study we will elucidate the molecular basis of the interactions between FADD and its binding partners using biochemical and biophysical studies. This research will improve our understanding of death receptor-induced apoptosis and the differences in signalling mechanisms. A detailed knowledge of these aspects of death receptor signalling is of significance because they represent critical regulatory steps that could be useful for targeted interventions.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
Structural And Drug Discovery Studies Of Oxidative Stress Regulator, Thioredoxin-interacting Protein
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
Toxic oxygen molecules known as Reactive Oxygen Species (ROS) are by-product of normal metabolism. The excess of ROS is damaging and is well known to contribute to ageing process and age-related diseases such as cancer, diabetic complications, immune-system decline, and cardiovascular conditions to name a few. The human body possesses several defense systems that protect us from the excess of ROS maintaining a healthy level of ROS. A down-regulator of one of this systems, a protein called TXNIP, ....Toxic oxygen molecules known as Reactive Oxygen Species (ROS) are by-product of normal metabolism. The excess of ROS is damaging and is well known to contribute to ageing process and age-related diseases such as cancer, diabetic complications, immune-system decline, and cardiovascular conditions to name a few. The human body possesses several defense systems that protect us from the excess of ROS maintaining a healthy level of ROS. A down-regulator of one of this systems, a protein called TXNIP, has been recently discovered. The amount of TXNIP is increased in such conditions as high glucose, a first sign of diabetes, and under ischemia, a shortage of blood supply occurring during heart attack. This weakens the anti-oxidant defense systems and makes the organism more vulnerable to ROS exposure. Our team of researchers embarked on structural and functional studies of TXNIP with the purpose to identify small molecules that can interfere with the undesirable action of TXNIP. These molecules might become useful therapeutic agents to counteract weakening organism's ROS defense system caused by TXNIP in many disease conditions such as, cancer, diabetes and cardiac failure.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