This research program aims to gain a detailed understanding of the organisation of the cell surface at the molecular level. The cell surface is organised into domains with distinct functions. Visualisation of these domains, identifying their important components, and understanding how they form and function will have huge importance for therapeutic strategies aimed at combatting the changes associated with cell transformation in cancer and in other human diseases such as muscular dystrophy.
The regulation to early T cell signalling is a critical step in immune responses. Superimposed onto the biochemical pathways is a spatial organization that defines the immunological synapse. My research aims to map the principles of the spatial organization on the molecular scale to identify how lipids could unbalance the dynamic signalling equilibrium, for example in obese patients. To achieve this goal, my research group has developed single molecule microscopy approaches.
A Signalling Endosomal Network In T Cell Activation
Funder
National Health and Medical Research Council
Funding Amount
$428,016.00
Summary
T lymphocytes play a central role in the adaptive immune response, which specifically targets pathogens and cancer cells and creates the immunological memory. Activation of sometimes as little as one single receptor on a T cell triggers a cellular signal that rapidly expands and branches out in a multitude of sub-signals. Here we will use a combination of novel microscopy approaches to visualise how a network of dedicated intracellular compartments is in charge of these processes.
Understanding The Role Of The Putative Phospholipid Translocase ATP11c In B Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$455,153.00
Summary
The immune system protects humans against recurrent infections with a wide range of pathogens. Formation of antibodies is a crucial element of the immune response. Defects in the production of antibodies can lead to recurrent and often life-threatening infections. This project seeks to understand a genetic defect in mice resulting in an almost complete absence of antibody producing cells, thereby causing a disease that is similar to some forms of human immunodeficiency.
I am a cell biologist determining how the organization of the plasma membrane influences signal transduction processes; my long-term goal is to understand the spatial–temporal organization of cell signalling.
How Lipids Affect Signalling Efficiencies In T Cells
Funder
National Health and Medical Research Council
Funding Amount
$472,882.00
Summary
A high fat diet can compromise the function our immune system. This project examines how lipids affect T cells. We propose that T cells from mice on a high fat diet can no longer respond to an immune challenge because the signalling processes that lead to activation are deregulated. We have established a new microscopy technique that allows us to measure the efficiency of signalling processes. We will use this method to identify which lipids contribute the most to T cell deregulation.
The cell is the building block of life. This proposal focusses on the surface of the cell, the plasma membrane, and specialised structures called caveolae that are an abundant feature of animal cells. Altered caveolae are a feature of many human disease conditions. In this proposal we will address the function of caveolae. We will test the idea that proteins are released from caveolae into the cell when cells are stressed forming a novel signalling pathway disrupted in disease.
Translating Membrane Proteins Into Therapeutics; From Bedside To Bench
Funder
National Health and Medical Research Council
Funding Amount
$9,466,000.00
Summary
Membrane proteins are the principal gatekeepers for control of cellular response, with G protein-coupled receptors (GPCRs) the largest family of cell surface proteins. These proteins are critically important for pathophysiological control, and are a major target for drug discovery. Nonetheless drug attrition due to lack of clinical efficacy remains high. We are combining cell biology, clinical management and drug discovery science to enable more effective therapeutic translation.
Peripheral Membrane Proteins In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$469,151.00
Summary
Peripheral membrane proteins are critical for processes such as cell transport, signaling, neurosecretion and development. As such, their dysfunction can lead to many debilitating diseases including cancer, inflammation and neurodegeneration. This project will establish fundamental new knowledge about how peripheral membrane proteins regulate cell function, how their perturbation or mutation results in human disease, and will inform efforts to target them for future therapeutic outcomes.
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