Characterisation Of Novel CDKL5 Targets: Implications For Rett Syndrome And Related Neurodevelopmental Disorders.
Funder
National Health and Medical Research Council
Funding Amount
$421,977.00
Summary
Rett syndrome (RTT) is the second most common cause of severe mental retardation in girls and women. Although two genes (MECP2 and CDKL5) responsible for RTT have been identified, we still do not understand how these genes affect brain function. The focus of this research project is to identify which proteins are controlled by CDKL5, with the express hope that a better understanding of these processes will allow us to design specfic therapies for this untreatable devasting disorder.
The Structural Basis Of Ligand-Induced Activation Of The Insulin Receptor
Funder
National Health and Medical Research Council
Funding Amount
$640,825.00
Summary
We aim to understand how insulin binds to and activates its cell-surface receptor. This information has implications for the design of anti-diabetic agents targetted directly to the insulin receptor. Diabetes is a global health problem and is classified by the World Health Organization as an epidemic. The results also have implications for the insulin-like growth factor receptor system and the design of anti-cancer therapeutics directed towards it .
Regulation Of Hedgehog Signalling Through Intracellular Trafficking Events
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which ....The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which operate to ensure that this complex pathway of interacting molecules functions correctly during embryonic development. By understanding how this regulation occurs we will gain valuable insight into how disruption of this pathway results in such a range of disease, as well as into how agents which modulate this pathway may potentially act in a therapeutic setting.Read moreRead less
Targeting Of The APC Tumour Suppressor To Mitochondria: Implications For APC Regulation And Cellular Function
Funder
National Health and Medical Research Council
Funding Amount
$390,116.00
Summary
Inherited mutations in the APC gene cause colon cancer, and kills 4,700 Australians every year. About 1 in 21 Australians develop colorectal cancer by the age of 75. APC mutations change cells in different ways, triggering the cancer process. We have discovered a new pathway, involving altered movement of APC to mitochondria in tumour cells. This study will investigate how this cancerous change may help our understanding of colon cancer progression.
Structural Basis Of Ligand Binding To Type 1 Insulin-like Growth Factor Receptor (IGF-1R)
Funder
National Health and Medical Research Council
Funding Amount
$446,562.00
Summary
Insulin-like growth factors are involved in normal growth and development. However, they are also implicated in cancer development and progression. We are seeking to understand the way in which these growth factors bind to their receptor on the surface of the cell and stimulate the cell to survive, proliferate and migrate to new tumour sites. Such knowledge will be useful in the design of molecules that could potentially intervere with this process and thus be used as anti-cancer therapeutics.
A hierarchical quantum mechanical and classical simulation of biological ion channels. I aim to develop a methodology incorporating molecular quantum
mechanics and classical Brownian mechanics in a way that can be
applied practically to large macromolecular systems, thus relating
fine structural details to experimentally measurable
properties. Specifically, I will apply this methodology to study ion
channels in which the challenge is to relate electronic and atomic
structure to the conduct ....A hierarchical quantum mechanical and classical simulation of biological ion channels. I aim to develop a methodology incorporating molecular quantum
mechanics and classical Brownian mechanics in a way that can be
applied practically to large macromolecular systems, thus relating
fine structural details to experimentally measurable
properties. Specifically, I will apply this methodology to study ion
channels in which the challenge is to relate electronic and atomic
structure to the conductance properties of the channel. Accurately
determining these relationships provides a pathway to developing cures
for many neurological, cardiac, and muscular diseases.
Read moreRead less
Structural Characterisation Of Phosphopeptide Recognition By FHA Domains
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
Cells require numerous signalling pathways to keep various cellular processes coordinated and under control. One of the most important aspects of signalling is formation of complexes involving two or more different proteins. One of the recently identified players in the formation of these signalling complexes is the so-called forkhead-associated (FHA) module, FHA modules are protein sequences of ~130 amino acids that appear as a part of signalling proteins and bind to specific sequences on signa ....Cells require numerous signalling pathways to keep various cellular processes coordinated and under control. One of the most important aspects of signalling is formation of complexes involving two or more different proteins. One of the recently identified players in the formation of these signalling complexes is the so-called forkhead-associated (FHA) module, FHA modules are protein sequences of ~130 amino acids that appear as a part of signalling proteins and bind to specific sequences on signalling protein partners. Many proteins containing FHA modules are important for the repair of damaged DNA and the stability of chromosomes. The aim of our studies is to understand the molecular and atomic details of how FHA modules bind their partners. This is the first step towards designing therapeutic agents against various forms of cancer where DNA is damaged.Read moreRead less
Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in ....Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in one of the components of this system. Proteins called small GTPases provide order for this traffic and allow specific cargo to reach specific destinations. They regulate cell functions by acting as switches, turning biochemical processes on and off inside the cell. Ral is a small GTPase enzyme found in brain and broadly distributed in other cells. We have discovered that Ral is part of a large signalling complex. When activated Ral stimulates effectors, either the exocyst or RalBP1. In turn, mild oxidative stress controls a Ral inhibitor protein called ERp57. The research proposed aims to establish the functional role for the Ral signalling complex in cells. We will determine with which vesicle trafficking events Ral is associated, which effector it utilises in that pathway, and how that effector directs the traffic. We will also map the steps that may lead to inactivation of Ral via ERp57 in cells, and propose that this is mediated by mild oxidative stress. Techniques of molecular biology, biochemistry, molecular biology, proteomics and microscopy will be used to establish these functions. The research will lead to increased knowledge of the significance of this protein to cellular and particularly neuronal cell function. This forms the basis for understanding normal cell function and for identification of further factors causing diseases of vesicle transport. In time, such research aids in the development of specific therapies for sufferers of such diseases.Read moreRead less
Regulated Shuttling Of Beta-catenin And IQGAP1 Between Nucleus And Plasma Membrane In Migrating Cells
Funder
National Health and Medical Research Council
Funding Amount
$511,703.00
Summary
Inherited gene mutations that cause colon cancer kill 4,700 Australians every year. About 1 in 21 Australians develop colorectal cancer by age 75. Activation of the beta-catenin protein is a critical switch in the path to colon cancer. We discovered that beta-catenin, and another protein it interacts with called IQGAP1, move between different cellular compartments. We plan to study this process in more detail, as it relates to how beta-catenin works and to understanding its role in cancer.