Location, Location, Location: Sub-cellular Specific Targeting Of JNK As A Novel Therapy In Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$633,755.00
Summary
The ‘triple negative’ breast cancer subtype is the most aggressive form of breast cancer, and unlike other subtypes, there are no drugs to specifically this subtype. While many potential drug targets have been identified, they cannot be utilised clinically because of other beneficial roles within the body. We are now deploying our innovative experimental platforms to specifically target the tumour promoting functions of a protein known as ‘JNK’, whilst retaining its beneficial functions.
Mechanical Factors In Normal Human Colonic Motility
Funder
National Health and Medical Research Council
Funding Amount
$650,023.00
Summary
Abnormal human colonic contractions cause significant medical, societal and financial burdens. Diagnosis and treatment of motility disorders requires an understanding of normal colonic contractility against which to measure dysfunction. Through state-of-the-art recording and analytical techniques, developed by the applicants, this project will provide the first clear description of normal human colonic motor patterns and how they are generated.
GTPase Regulation Of The Hippo Organ Size-control Pathway
Funder
National Health and Medical Research Council
Funding Amount
$570,334.00
Summary
The Hippo pathway is a key regulator of tissue growth. It was first discovered in vinegar flies and plays a similar role in mammals. We aim to define the mechanism by which two proteins, Pix and Git, control tissue growth by regulating the Hippo pathway. These studies will be performed in flies. Our studies will shed light on how tissue growth is controlled, and have the potential to inform the way that we treat human cancers and tissue growth disorders.
We have identified a microRNA (miRNA) which can elicit the functional outcome of the anti-inflammatory cytokine IL-10. miRNAs constitute a novel mechanism used by cells to regulate gene expression and have shown much promise as a therapeutic tool. Our finding suggests that modulation of miRNAs through the use of miRNA mimics or antisense technology may serve as an alternative and/or synergistic approach for the use of IL-10 as therapy in chronic inflammation.
Male fertility requires sufficient production of healthy sperm in the testis. We discovered that cells in the adult testis communicate via the Hedgehog (Hh) signalling pathway as sperm develop. We propose to use a highly specific drug to inhibit Hh activity in order to delineate the precise steps in sperm production affected by Hh signalling. We will study the importance Hh in maintenance of spermatogonial stem cells and create mouse models to learn how it is controlled.
Targeting The JNK-JUN Pathway To Overcome Therapy Resistance In Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$694,729.00
Summary
Melanoma patients can display remarkable responses to targeted and immunotherapies. However most patients progress rapidly on targeted therapies and only a small proportion respond to immunotherapies. We have found that combination treatment with JNK inhibitors can overcome therapy resistance. We will determine the most efficacious JNK inhibitors available, and the optimal dosing and scheduling of combination treatment for evaluation in patients to improve responses, outcomes and survival.
Despite aggressive treatment, the survival rate for high-risk neuroblastoma patients is below 50%. We recently found that these poor-outcome neuroblastomas have a defect in a key drug response pathway, called the JNK pathway. Standard-of-care neuroblastoma drugs all require the JNK pathway to kill neuroblastoma cells, although we have now identified alternative drugs that do not require JNK. We now plan to demonstrate the efficacy of these drugs in neuroblastomas with a defective JNK pathway.
Cellular Regulation Of Receptor Signalling And Cytokine Responses
Funder
National Health and Medical Research Council
Funding Amount
$859,288.00
Summary
Cell surface receptors and signalling pathways elicit the release of cytokines, or chemical messengers, to control inflammation, which is the body’s response to infection or danger. We have discovered a new signalling pathway that can turn off inflammation and help prevent inflammatory disease. Our studies will now define the molecular details of this pathway and show how new and existing drugs targeting this pathway can be optimally used to treat inflammation and cancer.
Skeletal Muscle Signal Transduction Related To Exercise, Metabolic Disease And Human Health
Funder
National Health and Medical Research Council
Funding Amount
$557,298.00
Summary
Exercise is one of the best prevention and treatment strategies for all major human diseases. Despite these well documented advantages, we still do not know exactly how exercise produces these benefits at the molecular level. A comprehensive understanding of this will lead to new avenues to treat many diseases. This project will monitor thousands of molecular changes that occur in human muscle biopsies following exercise and create the world’s first molecular blueprint of exercise.
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.