Neurons are highly compartmentalized cell-types. In neurodegenerative diseases such as Alzheimer's disease, the protein Tau that serves a distinct function in one cellular compartment (the axon) accumulates in a massively phosphorylated form elsewhere (somatodendritic compartments and their spines) which is believed to impair neuronal functions. We will investigate how Tau is distributed in health and disease, and determine how this distribution is regulated.
Role Of JNK And P38 MAPK Signalling In Diabetic Nephropathy
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
Renal failure is a major health problem in our community. Patients who progress to end-stage renal failure are dependent upon lifelong dialysis or transplantation (an expensive and complex treatment). The past decade has seen a dramatic increase in the number of patients developing end-stage renal failure, mainly due to increasing rates of diabetic kidney disease. Indeed, the recent AusDiab nationwide survey that identified diabetes or glucose intolerance (a precursor to diabetes) is now present ....Renal failure is a major health problem in our community. Patients who progress to end-stage renal failure are dependent upon lifelong dialysis or transplantation (an expensive and complex treatment). The past decade has seen a dramatic increase in the number of patients developing end-stage renal failure, mainly due to increasing rates of diabetic kidney disease. Indeed, the recent AusDiab nationwide survey that identified diabetes or glucose intolerance (a precursor to diabetes) is now present in up to 25% of the adult Australian population. Around 50% of diabetics develop kidney disease and, despite recent advances in better control of blood glucose and blood pressure, kidney disease in most diabetic patients will inexorably progress to end-stage renal failure. Therefore, there is an urgent need to improve treatment strategies in diabetic patients to avoid kidney failure. We have identified a group of proteins (enzymes called JNK and p38) within cells that play a causal role in the development of non-diabetic forms of kidney disease. Most recently, we have shown that an increase in the activity of these proteins (JNK and p38) is associated with the development of human and experimental diabetic kidney disease. Therefore, this project will block the action of JNK and p38 using two complementary approaches (pharmaceutical drugs and genetically modified mice) to determine whether targeting these proteins can suppress the development of diabetic kidney disease. In addition, there is evidence to suggest that blockade of these proteins may have a beneficial impact upon insulin resistance and elevated blood glucose in type 2 diabetes. If these postulates are proven, this will provide a well-defined therapeutic target for the treatment of diabetic kidney disease, and perhaps diabetes itself. Furthermore, since inhibitors of these proteins are already in clinical trials for other indications, targeting this mechanism in diabetic kidney disease is a realistic goal.Read moreRead less
Melanoma Resistance To Combination BRAF And MEK Inhibition Is Driven By Reprogramming Of MAPK Signaling
Funder
National Health and Medical Research Council
Funding Amount
$745,082.00
Summary
Until recently, patients with metastatic melanoma were treated with single agent chemotherapy drugs that produce response rates of less than 10%. New drugs targeting the mitogen activated protein kinase (MAPK) pathway have now shown significant activity, but nearly all patients treated with these new inhibitors eventually develop resistance and progress. This project utilises patient tumour samples to examine the mechanisms of resistance and ways of enhancing the targeted inhibition of the MAPK ....Until recently, patients with metastatic melanoma were treated with single agent chemotherapy drugs that produce response rates of less than 10%. New drugs targeting the mitogen activated protein kinase (MAPK) pathway have now shown significant activity, but nearly all patients treated with these new inhibitors eventually develop resistance and progress. This project utilises patient tumour samples to examine the mechanisms of resistance and ways of enhancing the targeted inhibition of the MAPK signaling cascade.Read moreRead less
New drugs targeting the immune system have dramatically improved the survival of melanoma patients. Nevertheless, 30-40% of patients responding to these new inhibitor will develop drug resistance. This project utilizes patient tumour samples to examine the mechanisms of acquired resistance to immune checkpoint inhibitors. This information will accelerate the identification of novel combination therapies to improve patient outcomes.
Manipulating Oncogene Addiction And Immunity In The Treatment Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$687,975.00
Summary
Melanoma is a major Australian health problem and a common cause of cancer death in young adults. Treatment of melanoma has been revolutionised in the last few years, but many patients fail to respond to new therapies or rapidly progress on treatment. This proposal examines the mechanisms that drive resistance to therapy and identifies markers predictive of clinical response. This approach will accelerate the development of new strategies and improve patient care by personalising treatment.
C-Jun N-terminal Kinase Actions In The Response To Stress
Funder
National Health and Medical Research Council
Funding Amount
$480,127.00
Summary
All cells in our body sense and respond to stressful changes in our environment. We are focused on enzymes called JNKs that relay this information, and so form part of the key response pathways. JNKs are now being evaluated as new drug targets for the treatment of diseases including diabetes and stroke, but we know very little about how JNKs work in stressed cells. We will define new partners for the JNKs and in so doing reveal new information on the stress-activated events they regulate.