Senataxin, A Novel Protein Involved In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. T ....The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. This disorder is called ataxia with oculomotor apraxia type 2 or AOA2. This condition develops in the teenage to early twenties and as the name suggests is characterised by loss of control of gait together with difficulties of eye movement. It is due to reduced function of a particular region of the brain called the cerebellum responsible for controlling movement. We have initial data suggesting that cells from these patients are very sensitive to environmental chemicals and their capacity to carry out repair of damage to DNA is compromised. We will investigate the nature of the defect at the molecular level and establish the function of the protein defective in this syndrome. This information will be important to determining specific therapies for AOA2 patients and may also have relevance to other neurodegenerative disorders.Read moreRead less
The co-expression of visual pigments in a single photoreceptor: environmental regulation and spectral tuning. The light sensitive cells (photoreceptors) in the vertebrate retina contain filters (oil droplets) and visual pigments (opsins). These structures tune the incoming light and initiate the visual process, respectively. Exciting new research reveals that some vertebrates express more than one opsin within a single photoreceptor. We plan to examine the regulation of single and two co-express ....The co-expression of visual pigments in a single photoreceptor: environmental regulation and spectral tuning. The light sensitive cells (photoreceptors) in the vertebrate retina contain filters (oil droplets) and visual pigments (opsins). These structures tune the incoming light and initiate the visual process, respectively. Exciting new research reveals that some vertebrates express more than one opsin within a single photoreceptor. We plan to examine the regulation of single and two co-expressed opsin genes by manipulating the light environment. We expect to determine the environmental triggers for visual pigment tuning and the effects of co-expression on colour vision.Read moreRead less
Environmental regulation of opsin expression and spectral tuning in the vertebrate retina. Exciting new evidence shows that the vertebrate visual system is extraordinarily plastic and that the colour and brightness of the ambient light regulates both the spatial and temporal expression of visual pigments (opsin) genes and the degree of spectral filtering in the retina. Based on findings that more than one visual pigment can be co-expressed in a single photoreceptor type, we plan to manipulate th ....Environmental regulation of opsin expression and spectral tuning in the vertebrate retina. Exciting new evidence shows that the vertebrate visual system is extraordinarily plastic and that the colour and brightness of the ambient light regulates both the spatial and temporal expression of visual pigments (opsin) genes and the degree of spectral filtering in the retina. Based on findings that more than one visual pigment can be co-expressed in a single photoreceptor type, we plan to manipulate the light environment in order to identify and quantify the effect of different lighting regimes by morphological, spectral and molecular techniques in a concerted effort to understand the regulation of opsin expression.Read moreRead less
The evolution of colour vision in vertebrates. Colour vision plays a crucial role in the lives of many animals including vertebrates. However, very little is known about the origins of colour vision and we aim to fill this gap. Photoreceptors (cone cells) with sensitivities to different colours mediate colour vision (humans possess blue, green and red cones). This study will examine the structure, physiological responses and molecular biology of these cells in the closest living relatives of the ....The evolution of colour vision in vertebrates. Colour vision plays a crucial role in the lives of many animals including vertebrates. However, very little is known about the origins of colour vision and we aim to fill this gap. Photoreceptors (cone cells) with sensitivities to different colours mediate colour vision (humans possess blue, green and red cones). This study will examine the structure, physiological responses and molecular biology of these cells in the closest living relatives of the early vertebrates. The underlying mechanisms for spectral tuning, the genetic rate of evolutionary change and the importance of colour in visual ecology will also be examined.Read moreRead less
Functions Of A Novel Conserved DNA Damage Response Protein Family In Telomere Stability
Funder
National Health and Medical Research Council
Funding Amount
$282,825.00
Summary
The free DNA ends of chromosomes, termed telomeres, generally resemble broken DNA. Because broken DNA is a major contributing factor to the onset of cancer, cells try to fix broken ends. However, in case of telomeres, such repair processes have to be prevented because otherwise different chromosomes would fuse with each other. Fused chromosomes are very fragile and cannot be evenly distributed between dividing cells, and are therefore another important trigger of cancer development. Therefore, c ....The free DNA ends of chromosomes, termed telomeres, generally resemble broken DNA. Because broken DNA is a major contributing factor to the onset of cancer, cells try to fix broken ends. However, in case of telomeres, such repair processes have to be prevented because otherwise different chromosomes would fuse with each other. Fused chromosomes are very fragile and cannot be evenly distributed between dividing cells, and are therefore another important trigger of cancer development. Therefore, chromosome ends are covered by a cap, which hides them from the DNA damage response machinery. From these considerations it is clear that there are close connections between the cellular DNA damage response and chromosome ends. Moreover, recently it has become clear that DNA damage proteins are also required to stop normal cells from growing, a process termed senescence. Senescence is a consequence of shortened chromosome ends, and does not occur in cancer cells. Altogether, it is clear that DNA breaks and senescence are two of the major questions for our understanding of cancer development. We have identified a novel conserved protein family that is involved in the response to DNA damage in yeast and humans. In addition, the yeast Mdt1 protein is a very sensitive indicator of changes in the telomere cap. Absence of proteins that organise the cap leads to the addition of several phosphate groups to the Mdt1 protein. We propose that phosphate-coupled Mdt1 prevents chromosome ends from fusion with each other, or from fusing with broken DNA ends after widespread damage. As a consequence, cells that have mild cap defects die at an >1000-fold increased rate in response to DNA damage when they also lack Mdt1. As part of this application we want to find out the precise mechanism by which Mdt1 stabilises chromosome ends, and test our hypothesis that the corresponding human protein termed ASCIZ also has similar functions in protecting chromosome ends.Read moreRead less
Specification of the nerve cell subtypes in the developing central nervous system. Different subtypes of nerve cells in the brain, which carry out distinct functions, are generated in the embryo by the co-ordinated action of many genes. This project aims to use the genetic advantages of the zebrafish to determine the role of genes in specifying the final fates of nerve cells in the retina, which analyses visual signals within the eye.
Elucidating the neural pathways and genetic basis of speech. The project will elucidate the biological basis of speech, a unique feature of the human condition. The project will do this by i) discovering genes associated with speech disorder and ii) defining the neural pathways associated with speech production. This study will address critical questions regarding gene, brain and behaviour relationships in speech.
Discovery Early Career Researcher Award - Grant ID: DE120101311
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Role of intrinsic versus extrinsic cues in cell type determination during development and regeneration. During development all of the different cell types are generated by the action of genes and also signals from the embryo that read out which cell types are present or missing. This project studies how much environmental signals affect cell type generation developmentally and if they can be used to regenerate only the types missing in different diseases.
Drinking from the fire hose - Making sense of high density genetic and genomic data. The project will improve our understanding of the genetic component of common complex diseases such as cancer. Identification of genetic variants underlying disease risk is currently one of the primary means for increasing our understanding of the biochemical and developmental pathways involved. Genetic studies rely on sophisticated statistical and computational (bioinformatics) techniques. This project centres ....Drinking from the fire hose - Making sense of high density genetic and genomic data. The project will improve our understanding of the genetic component of common complex diseases such as cancer. Identification of genetic variants underlying disease risk is currently one of the primary means for increasing our understanding of the biochemical and developmental pathways involved. Genetic studies rely on sophisticated statistical and computational (bioinformatics) techniques. This project centres on the development, refinement and application of novel statistical analysis methods in genetics. Future advances in statistical and computational methods are essential if we are to exploit the large volumes of genome data now being generated to help develop diagnostics and interventions to improve public health.Read moreRead less