Many of the most serious diseases of Western societies including obesity, Type 2 diabetes, cancer growth and metastasis and cardiovascular disease have metabolic dimensions. The enzyme AMPK regulates cellular and whole body energy homeostasis by coordinating metabolic pathways to balance energy demand with nutrient supply. We are studying the structure and function of AMPK with the aim of better treating metabolic diseases.
Molecular Basis For Stress-induced Gene Regulation—a Model System To Understand Transcriptional Deregulation In Cancer And Neurological Disease
Funder
National Health and Medical Research Council
Funding Amount
$384,076.00
Summary
Deregulated gene transcription plays a critical role in cancer formation. It is therefore important to understand the molecular basis of gene transcription and how tumour cells hijack the process. In this Project, we will study the molecular basis of stress-inducible gene expression. This is particularly important for understanding the molecular basis of cancer as stress-inducible genes are activated by transcription factors implicated in breast, colon, lung, and prostate cancers.
Structural Characterisation Of The Co-inhibitory Complex Formed By The Tumour Suppressor PTEN And The Metastatic Factor PREX2
Funder
National Health and Medical Research Council
Funding Amount
$563,602.00
Summary
Metastasis is a major cause of cancer mortality. Characterisation of key proteins that regulate metastasis is therefore a priority. PTEN and PREX2 are enzymes that play key roles in metastasis in melanoma, and other cancers. We will determine the structural basis of PTEN:PREX2 co-inhibition, and determine how cancer-associated PREX2 mutations dysregulate this inhibitory complex. This study will provide the necessary knowledge for future drug development programs targeting PTEN:PREX2 in cancer.
Resolving And Targeting The Complex Molecular Mechanisms Underlying GPCR Signalling
Funder
National Health and Medical Research Council
Funding Amount
$1,071,370.00
Summary
Receptors are located on the surface of all human cells to allow our cells to respond to their environment. Over 30% of prescription drugs act through particular receptors called GPCRs, however effective drugs without side effects are difficult to develop because we do not have a deep understanding of how GPCRs transmit complex signals. In this proposal we seek to resolve the atomic-level details of GPCR signalling to assist in the development of better drugs for a diverse range of diseases.
A Structural Understanding Of Class B G Protein-coupled Receptor Function
Funder
National Health and Medical Research Council
Funding Amount
$1,289,570.00
Summary
G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins that enable communication from external signals to the inside of cells of the body. Class B GPCRs are a therapeutically important subclass of these receptors and they play crucial roles in bone and energy homeostasis, cardiovascular control and immune response. This grant will uncover fundamental knowledge on how these receptors work, and will enhance future development of therapeutics.
Assembly And Function Of Two Interacting Oncogenic Scaffolds
Funder
National Health and Medical Research Council
Funding Amount
$705,585.00
Summary
Aberrant signaling by the protein kinase superfamily is a known driving force for many cancers and inflammatory diseases. Recently, a subset of kinase-like proteins, termed pseudokinases, have emerged as crucial regulators of kinase signalling pathways. This proposal focuses on elucidating the scaffolding function and assembly of two pseudokinases, termed SgK223 and SgK269, which display oncogenic properties and aims to understand how their signalling abilities are subverted in a disease state.
Design And Engineering Of Adnectins For Diagnosis And Therapy
Funder
National Health and Medical Research Council
Funding Amount
$803,152.00
Summary
This project aims to engineer a naturally-occurring human protein, called an adnectin, to produce molecules that are able to bind specific targets in the human body, and as such may be used in the diagnosis and therapy of a range of diseases.
Signaling Pathways To Enhance Potency Of AMPK-targeting Drugs
Funder
National Health and Medical Research Council
Funding Amount
$661,966.00
Summary
Sedentary lifestyles and consumption of high energy foods has led to epidemics of obesity-related metabolic diseases that place enormous financial and medical burden on the Australian economy. An attractive drug target to treat these diseases is AMP-activated protein kinase (AMPK) which functions as both a cellular fuel gauge and co-ordinator of whole-body metabolism. Our goal is to improve AMPK drug potency by identifying novel processes that sensitize AMPK to drugs.
Genomic Analysis Of DNA Binding And Gene Regulation By The Chromatin Remodelling Factor UBF
Funder
National Health and Medical Research Council
Funding Amount
$624,254.00
Summary
Synthesis of ribosomes, the cellular protein synthetic machinery, is the major anabolic event of a growing cell and is frequently dysregulated during disease such as cancer. This grant will examine a protein termed UBF that we think plays an important role in orchestrating the cellular response to dysregulated ribosome biogenesis. By understanding how UBF functions we hope to uncover novel therapeutic approaches to treat diseases associated with ribosome stress .
Spatial And Temporal Dimensions Of Mu-opioid Receptor Signalling: Implications For The Development Of Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$799,316.00
Summary
The use of morphine as an analgesic is still limited by undesirable side effects such as tolerance. Despite decades of research, the mechanisms behind the development of tolerance are poorly understood. The ? opioid receptor is a protein expressed at the surface of the cells that is the target of morphine. This project will investigate the signalling events triggered by opioids with unprecedented resolution and will aim to elucidate why morphine elicits more tolerance than other opioid drugs.