Noncoding RNAs As Prognostic Markers And Therapeutic Targets In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$550,283.00
Summary
Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our labo ....Normal human development involves a symphony of genetic changes that control the growth and differentiation of different types of cells during embryogenesis. For many years it has been assumed that most genetic information is transacted by proteins, and that the remaining 98% of the human genome that does not encode proteins was (apart from a limited amount of associated regulatory elements) largely non-functional evolutionary junk. However, this may not be the case. Recent results from our laboratory and others have shown that most of our genome and that of other mammals is actually expressed as noncoding RNA, which appears to be developmentally regulated. These RNAs (of which there appear to be tens of thousands, well outnumbering the protein-coding mRNAs) have been referred to as the hidden layer or dark matter of our genome, as they have barely been studied, but appear to play a central role in both normal and abnormal development in humans. There is now increasing evidence that many noncoding RNAs, including small regulatory RNAs called microRNAs, are perturbed in cancer and that these perturbations may be directly involved in, and be an accurate indicator of, cancer state and the direction of cancer progression. If this is true we need to understand the expression and functions of these RNAs in order to develop better diagnostics and perhaps powerful new therapeutics for cancer, based on RNA technology and generic delivery systems. This project will explore the patterns of noncoding RNA expression in normal breast development and in breast cancer, to identify those RNAs that direct or accompany the differentiation of these tissues, and to test the effects of interfering with their expression on these processes. These foundation studies lie at the leading edge of a new understanding of human genetics and cancer, and will provide a platform for future applications in medicine that utilize this information and understanding.Read moreRead less
Genetic variation of single cell transcriptional heterogeneity in HiPSCs. This project aims to investigate whether induced pluripotent stem cells (iPSC) can be used to study the functions of genetic variants associated with human phenotypes and cell fate decisions. The project will utilise technology to produce single cell RNA sequence data for 100,000s of cells. By sequencing individual cells, the genetic control of cellular heterogeneity both within and between cells can be identified, and in ....Genetic variation of single cell transcriptional heterogeneity in HiPSCs. This project aims to investigate whether induced pluripotent stem cells (iPSC) can be used to study the functions of genetic variants associated with human phenotypes and cell fate decisions. The project will utilise technology to produce single cell RNA sequence data for 100,000s of cells. By sequencing individual cells, the genetic control of cellular heterogeneity both within and between cells can be identified, and in doing so, will provide significant benefit by revealing the potential for iPSC to be used for functional translation of human genomics.Read moreRead less
Molecular function of the ribonucleic acid binding protein RBM47 in embryonic and mature endoderm cells. This project aims to test the hypothesis that a novel ribonucleic acid (RNA) binding protein, called RBM47, regulates the processing of the RNA transcripts of genes. This project will reveal the identity and the function of these genes that are essential for controlling the growth of the embryo and the organism after birth.
Road rules for traffic on DNA - gene regulation by encounters between transcribing RNA polymerases and DNA-bound proteins. This project addresses a widespread but poorly understood phenomenon in gene regulation. The work will support Australian industries by supplying new tools for manipulation of gene expression for industrial and medical applications and will provide unique opportunities for Australian students in this emerging field.
Sprouting Angiogenesis and its Role in Development of Chamber Myocardium. The project aims to investigate how heart chambers form by testing the hypothesis that morphogenesis of the muscular walls of the heart is regulated during development by a Notch signalling-dependent process akin to angiogenic sprouting in other vascular beds. The project outcomes may have implications for diagnosis of congenital heart disease and for the fields of cardiac tissue engineering and regeneration. The project p ....Sprouting Angiogenesis and its Role in Development of Chamber Myocardium. The project aims to investigate how heart chambers form by testing the hypothesis that morphogenesis of the muscular walls of the heart is regulated during development by a Notch signalling-dependent process akin to angiogenic sprouting in other vascular beds. The project outcomes may have implications for diagnosis of congenital heart disease and for the fields of cardiac tissue engineering and regeneration. The project plans to elucidate cellular and molecular pathways underlying heart chamber development in mice using contemporary genetic methods, molecular embryology and imaging. Benefits may include a new framework for understanding heart development and disease, and the future application of this knowledge to translational cardiology.Read moreRead less
RNA-based analysis for prediction of islet death in diabetes. Death of insulin-producing cells is a common feature in diabetes. Presently, a blood glucose test remains the only blunt instrument to diagnose diabetes. The RNA-based analysis for prediction of islet death in diabetes (RAPID) study links with eight clinical trials to test this newly developed non-invasive assay for predicting diabetes. Early diagnosis will help to reduce diabetic complications in later life.
Ageing and the muscle stem cell niche. Adult stem cells are critical for repair and maintenance of tissues and ageing tissues show reduced stem cell function. This project will focus on how ageing leads to disruption of communication between muscle stem cells and their niche. The project aims to identify new therapeutic targets for age-related muscle wasting and reduced mobility in the elderly.
Control points in nitrogen uptake: enhancing the response of cereals to nitrogen supply and demand. Vast amounts of nitrogen fertiliser are applied to cereal crops to maintain yields. By uncovering what limits nitrogen uptake in cereals, this project will provide the scientific basis for improving nitrogen use efficiency and decreasing fertiliser use, with significant economic and environmental benefits.
Heads or tails - which did echinoderms lose in the evolution of radial symmetry? Echinoderms, despite their unusual radial body plan, are closely related to chordates, but it is not known how this plan evolved. This project uses gene expression studies with uniquely suited Australian species to identify genes involved in radial body plan development and generate insights into origins of chordates and the vertebrate central nervous system (CNS).
Genetic control of germline progenitor cell heterogeneity and fate. Tissue maintenance in adults is dependent on resident stem cells, defined by self-renewal and differentiation capabilities. It is apparent that stem cell populations are heterogeneous, being composed of subpopulations with distinct properties. The functional significance of these subsets and mechanisms that control their divergent characteristics are unclear. Using germline stem cells from mice as a model, stem cell subsets have ....Genetic control of germline progenitor cell heterogeneity and fate. Tissue maintenance in adults is dependent on resident stem cells, defined by self-renewal and differentiation capabilities. It is apparent that stem cell populations are heterogeneous, being composed of subpopulations with distinct properties. The functional significance of these subsets and mechanisms that control their divergent characteristics are unclear. Using germline stem cells from mice as a model, stem cell subsets have been identified based on differential expression of the pluripotency gene Pou5f1. This project aims to define functional characteristics of these subpopulations and to dissect transcription factor networks controlling their development. This promises important insights into understandings of adult stem cell regulation.Read moreRead less