Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel wh ....Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the immune system. These channels are unusual in that they can move between two states: a soluble state and a state that resides in the cell membrane. We have determined the first structures of this class of channel in both the soluble state and what is believed to be the membrane docking state. This has given us the first atomic picture of how this channel protein can alter its structure so as to carry out its function. In this project, we will determine: how the protein completes the transition into the membrane state; the structures of other key members of this class of channel protein; complexes between channel proteins and other cellular proteins; and the structure of the protein in the membrane state. We will also determine how several drugs control the activity of this channel. The results of our work will have specific implications for our channel and will serve as a paradigm other members of this new class of chloride channel. Understanding how this channel functions and how the current drugs control it will lead to the development of a new class of therapeutic agents that will control these channels by preventing the transition from the soluble to the membrane state.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
REGULATION OF MICROTUBULE DYNAMICS BY LIM KINASE1 (LIMK1)
Funder
National Health and Medical Research Council
Funding Amount
$386,020.00
Summary
Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. We have found that LIMK1 is very important in controlling the polymerisation of one of the most ....Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. We have found that LIMK1 is very important in controlling the polymerisation of one of the most abundant molecules in the cell, actin. We have now preliminary data to show that LIMK1 also controls another important cellular protein, tubulin. Changes in tubulin polymerisation are of extreme importance for cell division and drugs affecting the state of tubulin are very potent as anti-cancer drugs. The goals of this research are: (1) To confirm that LIMK1 regulates the polymerisation of tubulin and (2) To demonstrate that LIMK1 regulates tubulin polymerisation by controlling the activity of p25, a protein involved in tubulin polymerisation that is modified by LIMK1. The results from this research will be highly significant because LIMK1 is a novel drug development target. Drugs that inhibit this protein may block the ability of tumours to invade and metastasise. Therefore, we have to identify the other functions of LIMK1 to eliminate the possibility that drugs that inhibit LIMK1 and metastasis don't affect other organs and cells in the body. New molecules regulated by LIMK1 may also be suitable targets for drug development because through their inhibition we may also regulate other LIMK1 activities and possibly metastasis.Read moreRead less
The Role Of Intersectin-1 In Endocytic Anomalies: Implications For Down Syndrome And Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$510,500.00
Summary
Individuals with Down syndrome have three copies of human chromosome 21, rather than the normal two. We have discovered a gene called Intersectin-1, located on human chromosome 21, that is expressed at higher levels than normal in individuals with Down syndrome. Intersectin-1 has a role in endocytosis, a process whereby cells take up molecules from the outside. Endocytosis occurs in all cells but is highly specialised in the brain where chemical transmitters are released and then rapidly recover ....Individuals with Down syndrome have three copies of human chromosome 21, rather than the normal two. We have discovered a gene called Intersectin-1, located on human chromosome 21, that is expressed at higher levels than normal in individuals with Down syndrome. Intersectin-1 has a role in endocytosis, a process whereby cells take up molecules from the outside. Endocytosis occurs in all cells but is highly specialised in the brain where chemical transmitters are released and then rapidly recovered by endocytosis in a process enabling neurones to pass signals to one another. A disturbance in endocytosis has been reported as the earliest hallmark of Alzheimer's disease in both non-Down syndrome and Down syndrome individuals. This disturbance is characterised by the presence of enlarged endosomes (small packages in neuronal cells containing chemical neurotransmitters formed during endocytosis). These enlarged endosomes are present long before the characteristic plaques of Alzheimer's disease appear. Since all individuals with Down syndrome develop Alzheimer's-like neuropathology, there must be a common disease mechanism that can be traced to the extra gene dosage from chromosome 21. We propose that a malfunctioning of Intersectin-1 is this common mechanism and we aim to test our hypothesis by the generation and analysis of mouse models of disrupted endocytosis.Read moreRead less
The Regulation Of Gene Expression During Adipogenesis
Funder
National Health and Medical Research Council
Funding Amount
$549,446.00
Summary
The body stores energy acquired from ingested food as fat droplets within storage cells termed adipocytes. The amount of fat varies between individuals and may also vary during an individual's life. The variations reflect differences in physiology, diet, and behaviour and have been the focus of intense study. Excessive accumulation of fat is a serious health problem as it is associated with conditions such as heart disease and diabetes. This grant application primarily concerns using a new line ....The body stores energy acquired from ingested food as fat droplets within storage cells termed adipocytes. The amount of fat varies between individuals and may also vary during an individual's life. The variations reflect differences in physiology, diet, and behaviour and have been the focus of intense study. Excessive accumulation of fat is a serious health problem as it is associated with conditions such as heart disease and diabetes. This grant application primarily concerns using a new line of genetically modified mice that have reduced fat. These mice lack a key gene regulatory protein that is implicated in fat accummulation and adipocyte formation. It is expected that a knowledge of the genes regulating the formation and function of fat storage cells will contribute to new strategies for controlling fat formation and will help in the prevention of diseases such as diabetes and heart disease.Read moreRead less