Failure-to-progress In Human Labour Results From A Profound Electrical Negativity Of The Uterine Cells: Targeting The Ion Channels Involved
Funder
National Health and Medical Research Council
Funding Amount
$564,541.00
Summary
The incidence of failure to progress in labour has increased in recent years, being linked to the rise in obesity. The result is a significant escalation in the rate of delivery by Caesarean Section (CS) which increases the risk of serious complications during subsequent pregnancies. We have identified dysfunctional systems associated with poor uterine contraction. We now aim to determine the mechanisms underlying these dysfunctional systems to lay the foundations for better therapeutics.
Molecular Basis Of Voltage Dependent-activation Of HERG K+ Channels
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
The rhythm of the normal heart beat is controlled by electrical signals mediated by the flow of electrically charged atoms called ions. The flow of ions across heart cell membranes is predominantly mediated by proteins called ion channels that open and close in response to changes in the voltage across the cell membrane. One of these channels, called the HERG channel, has some unusual properties. Most notably, HERG channels open very slowly following an electrical stimulus, so slowly that they d ....The rhythm of the normal heart beat is controlled by electrical signals mediated by the flow of electrically charged atoms called ions. The flow of ions across heart cell membranes is predominantly mediated by proteins called ion channels that open and close in response to changes in the voltage across the cell membrane. One of these channels, called the HERG channel, has some unusual properties. Most notably, HERG channels open very slowly following an electrical stimulus, so slowly that they do not fully open until the end of the cardiac contraction cycle. These channels are therefore particularly well placed to help suppress arrhythmias initiated by premature or ectopic beats. We propose to undertake a detailed investigation into the mechanisms by which HERG channels open and close and to determine why activation of these channels is so slow. These results will provide a greater understanding of how HERG channels work and how the normal activity of HERG channels helps to suppress abnormal heart rhythms.Read moreRead less
Regulation Of The Sarcolemmal Na-K Pump By FXYD Proteins
Funder
National Health and Medical Research Council
Funding Amount
$268,264.00
Summary
Background. Pump molecules embedded in the membranes of all cells maintain a difference in composition between the cell content and the surrounding tissue fluids. Of these, the membrane sodium-potassium pump (Na+-K+ pump) is the most important. It uses metabolic energy generated in the cell to transport 3Na+ out in exchange for 2K+ transported in, and maintains a low concentration of Na+ and a high concentration of K+ within cells. The opposite applies to the surrounding tissue fluids. The conce ....Background. Pump molecules embedded in the membranes of all cells maintain a difference in composition between the cell content and the surrounding tissue fluids. Of these, the membrane sodium-potassium pump (Na+-K+ pump) is the most important. It uses metabolic energy generated in the cell to transport 3Na+ out in exchange for 2K+ transported in, and maintains a low concentration of Na+ and a high concentration of K+ within cells. The opposite applies to the surrounding tissue fluids. The concentration gradient for Na+ serves in mechanisms that couple transport of other ions and molecules to the downhill movement of Na+ in the direction determined by its concentration gradient. The transport of ions and molecules directly and indirectly due to the operation of the membrane Na+-K+ pump is very important for the function of all cells. Objectives. It is poorly understood how cells regulate the activity of their membrane Na+-K+ pumps. We will examine if small molecules (FXYD proteins) in the cell membrane, closely associated with the pump, regulate its activity. Methods. We will use a whole-cell patch clamping technique to attach small glass pipettes to single heart cells and replace their content with solutions in the pipettes. The technique allows real-time measurement of Na+-K+ pump activity because the 3:2 Na+:K+ exchange ratio generates an electrical current that can be measured in the single cells. The FXYD proteins will be produced in bacteria, purified and introduced into the heart cells by inclusion in the pipette solution that replace the cell content. Expected outcomes. Achieving this project's objectives will greatly enhance our understanding of Na+-K+ pump regulation. This is important because high levels of Na+ in heart cells is a pivotal abnormality in heart disease. Understanding the Na+-K+ pump can be activated to reduce cell Na+ levels should help design of treatments.Read moreRead less