Functional Analysis Of The Molecular Switch That Regulates ADAM10-mediated Cleavage Of RTK Ligands In Tumour Cells.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive tumours. The switch to cell repulsion occurs by cleavage of th ....We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive tumours. The switch to cell repulsion occurs by cleavage of the ephrin by ADAM10 which also functions in other cancer promoting events by cleaving growth factors. Our structure reveals how Eph-bound ephrin is specifically targeted by ADAM. We will now determine the relevance of this mechanism for other ADAM10 targets, and design drugs to bind this region and inhibit ADAM function, which we will test in assays measuring tumour cell movement and growth, with the aim of developing therapies to block cancer progression.Read moreRead less
Cytoprotection By Erythropoietin In Hypoxia-ischaemia Of The Kidney And Brain
Funder
National Health and Medical Research Council
Funding Amount
$477,661.00
Summary
We aim to make a significant research impact by describing the complex mechanisms responsible for protecting kidney and brain cells from stress caused by a lack of oxygen. In particular we will establish whether the compound erythropoietin (Epo), which occurs naturally in the human body but its human recombinant form can also be used as a treatment, may be useful in protecting cells from death following a shortage of oxygen. . We have already described how Epo can protect the kidney, but no one ....We aim to make a significant research impact by describing the complex mechanisms responsible for protecting kidney and brain cells from stress caused by a lack of oxygen. In particular we will establish whether the compound erythropoietin (Epo), which occurs naturally in the human body but its human recombinant form can also be used as a treatment, may be useful in protecting cells from death following a shortage of oxygen. . We have already described how Epo can protect the kidney, but no one has yet described its action on kidney cell differentiation or its effect on structural and vascular support in the injured kidney. When might Epo treatment be effective? Could it protect against chronic renal disease? Likewise, whilst more very pre-term babies survive, this is a crucial period when they are at heightened sensitivity to lack of oxygen and they are at risk of brain damage and poor development because of lack of maturation of key structural cells in the brain. The role of Epo in aiding brain cell maturation and on blood vessel formation and function in this faulty development period is not known. Both of these health problems are major issues causing huge costs to society both financial and emotional. Despite the early evidence of a useful role for Epo in human disease treatment, current experimental and clinical data demonstrate the importance of further thorough investigation of mechanisms and cellular pathways that will underpin improvements in clinical outcomes. A particular strength of our project is that by comparing similarities and differences in the kidney and brain, we will be able to elucidate the mechanisms of action of Epo and its analogues.Read moreRead less
Infectious diseases are one of the leading causes of death and morbidity worldwide. In the last two decades the incidence of diseases caused by bacteria has increased dramatically with old pathogens re-emerging, often in a more virulent form, and new infectious agents appearing. Many pathogenic microbes are becoming increasingly resistant to antibiotics so that the need for new therapeutic targets is urgent. We will develop new antimicrobial chemotherapies by targeting DsbA, a specific factor in ....Infectious diseases are one of the leading causes of death and morbidity worldwide. In the last two decades the incidence of diseases caused by bacteria has increased dramatically with old pathogens re-emerging, often in a more virulent form, and new infectious agents appearing. Many pathogenic microbes are becoming increasingly resistant to antibiotics so that the need for new therapeutic targets is urgent. We will develop new antimicrobial chemotherapies by targeting DsbA, a specific factor involved in the generation of bacterial virulence. This protein is found in most bacteria and contributes to pathogenicity by promoting the formation of toxins and virulence factors. We will design specific inhibitors of DsbA by using a structure-based approach, implementing the leading edge technologies of fragment-based lead discovery by crystallography and NMR. We will then optimise the fragments to develop lead compounds and evaluate their suitability as DsbA inhibitors by in vitro and in vivo assays.Read moreRead less
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0882382
Funder
Australian Research Council
Funding Amount
$245,000.00
Summary
Biophysical Characterisation Facility. The protein analysis facility will have substantial benefits for basic science and biotechnology. It will create capacity for South Australian researchers to study proteins at the biophysical level. The facility will support research projects within the designated national research priority areas of 'Frontier technologies for building and transforming Australian industries' and 'Promoting and maintaining good health
Molecular Investigations into Polyglutamine Repeat Proteins. The proposed research program, will provide significant fundamental insight into the processes that control protein aggregation and disease. Investigating processes central to protein aggregation is important, as it will further our understanding of these critically-important events and our understanding of disease processes. Such knowledge will increase Australia's international research standing, as well as having the potential to ....Molecular Investigations into Polyglutamine Repeat Proteins. The proposed research program, will provide significant fundamental insight into the processes that control protein aggregation and disease. Investigating processes central to protein aggregation is important, as it will further our understanding of these critically-important events and our understanding of disease processes. Such knowledge will increase Australia's international research standing, as well as having the potential to generate novel therapies, that prevent neurodegeneration.Read moreRead less
Analysing the detrimental effects of polyglutamine expansion. The proposed research program, will provide significant fundamental insight into the processes that control protein aggregation and its link with disease. Investigating processes central to protein aggregation is important as it will deepen our understanding of how proteins inappropriately change shape and our understanding of disease processes. Such knowledge will increase Australia's international research standing, as well as ha ....Analysing the detrimental effects of polyglutamine expansion. The proposed research program, will provide significant fundamental insight into the processes that control protein aggregation and its link with disease. Investigating processes central to protein aggregation is important as it will deepen our understanding of how proteins inappropriately change shape and our understanding of disease processes. Such knowledge will increase Australia's international research standing, as well as having the potential to generate novel therapies, that prevent neurodegeneration.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