Regulating The Secretion Of Inflammatory Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$558,441.00
Summary
Cytokines or chemical messengers released by cells are essential for controlling immune responses but, in excess, they cause Crohn's disease and arthritis. Our research aims to block cytokine release as a novel way to ameliorate disease. We have identified specific cellular proteins, called golgins, that can be targeted to reduce cytokines. Here, characterization of golgin mediated cytokine transport in cells and in a mouse disease model is necessary to translate these findings for human benefit
Cytokine Secretion: A Model For Protein Trafficking.
Funder
National Health and Medical Research Council
Funding Amount
$204,111.00
Summary
TNF-a is an inflammatory cytokine with important roles in host defense, tumour regulation and energy homeostatis, however the oversecretion of TNF-a is also a major cause of septic shock, rheumatoid arthritis, Chron?s disease and the cachexia of cancer. TNF-a synthesis and its release from the surface of cells are relatively well understood. However little is known about its trafficking through the secretory pathway of cells. Understanding this process has the potential to provide new ways of co ....TNF-a is an inflammatory cytokine with important roles in host defense, tumour regulation and energy homeostatis, however the oversecretion of TNF-a is also a major cause of septic shock, rheumatoid arthritis, Chron?s disease and the cachexia of cancer. TNF-a synthesis and its release from the surface of cells are relatively well understood. However little is known about its trafficking through the secretory pathway of cells. Understanding this process has the potential to provide new ways of controlling the secretion of TNF-a. In previous work we have characterized transport vesicles and cytoskeletal proteins involved in secretory pathways of epithelial cells. We now propose to focus on the characterization of transport vesicles, and the roles of actin and myosins involved in TNF-a secretion in macrophages. These studies will rely on introducing new technology to this line of research. Fluorescent tagged constructs of TNF-a will be expressed and viewed in living cells to analyse the secretory pathway and measure the transport of TNF-a from its site of accumulation in the Golgi complex to the cell surface. This work aims to identify membrane-bound vesicles and vesicle-associated proteins that target TNF-a for secretion. We will begin to investigate the role of actin and myosins, using drugs and microinjected peptides to block their function. Overall these studies will provide important cell biological information about protein trafficking in cells. Cytokine secretion is important in immunity and cancer, information important to both fields will be gained from these studies.Read moreRead less
Regulators Of G Protein Signalling On The Golgi Complex
Funder
National Health and Medical Research Council
Funding Amount
$666,116.00
Summary
The secretion of proteins from cells involves a host of regulatory and signalling proteins. G proteins, signal transducers, located on the Golgi membranes, participate in the budding of transport vesicles in the secretory pathway. A newly-discovered family of Regulators of G Protein Signalling (RGS) proteins perform the critical function of turning off signals generated by G proteins. RGS proteins are powerful, but as yet, ill-defined regulatory molecules. In this study we will identify and char ....The secretion of proteins from cells involves a host of regulatory and signalling proteins. G proteins, signal transducers, located on the Golgi membranes, participate in the budding of transport vesicles in the secretory pathway. A newly-discovered family of Regulators of G Protein Signalling (RGS) proteins perform the critical function of turning off signals generated by G proteins. RGS proteins are powerful, but as yet, ill-defined regulatory molecules. In this study we will identify and characterize RGS proteins in macrophages that are located on Golgi membranes and help to regulate cytokine secretion and other immune functions. More detailed studies on selected RGS proteins will include mutational analysis of functional domains within the proteins and identification of other proteins that interact with RGS proteins. Overall these studies will lead us to understand how specific RGS proteins interact with G proteins and other molecules to regulate signalling in the secretory pathway. Anomalies in cell signalling have severe consequences in a variety of diseases and can cause cancer. Similarly, abnormal secretion in cells contributes to inflammation, diabetes and other disease processes. Information forthcoming from our studies on RGS proteins will have wide-reaching implications and the potential to reveal new targets for therapeutics in these diseases.Read moreRead less
Block Of ER-Golgi Vesicular Transport By Alpha-Synuclein As An Underlying Cause Of Parkinson's Disease.
Funder
National Health and Medical Research Council
Funding Amount
$361,091.00
Summary
Parkinson's disease, a progressive disorder of the central nervous system, is the most common neurodegenerative disorder after Alzheimer's disease. Parkinson's Disease is the direct result of the loss of dopamine producing cells in a portion of the brain called the substantia nigra. The loss of dopamine, a chemical messenger responsible for transmitting signals within the brain causes critical nerve cells in the brain to fire out of control, leaving patients unable to direct or control their mov ....Parkinson's disease, a progressive disorder of the central nervous system, is the most common neurodegenerative disorder after Alzheimer's disease. Parkinson's Disease is the direct result of the loss of dopamine producing cells in a portion of the brain called the substantia nigra. The loss of dopamine, a chemical messenger responsible for transmitting signals within the brain causes critical nerve cells in the brain to fire out of control, leaving patients unable to direct or control their movement in a normal manner. A protein, alpha synuclein has been shown to be a central component in Parkinson's disease. Our recent data, in collaboration with international colleagues, has led us to propose a new model for the mechanism by which alpha synuclein may cause Parkinson's disease that involves alpha synuclein interfering with how other proteins are transported within the cell. This proposal comprises a series of biomolecular experiments designed to test this model and provide new insights into therapies for Parkinson's patients.Read moreRead less