The migration of cancer cells (metastasis) is responsible for most cancer deaths. Central to this is dynamic organisation of the actin cytoskeleton _ an internal structure that provides cell shape and enables movement. We have identified a family of small molecules (called miR-200) that regulates this actin cytoskeleton through specifically downregulating various genes. We are investigating the nature of these genes and their role in cell motility _ an underlying pre-requisite of metastasis.
The Impact Of Granzyme B On Cytotoxic T Cell Migration Through Tissue
Funder
National Health and Medical Research Council
Funding Amount
$605,963.00
Summary
Cytotoxic T cells (CTL) are white blood cells that move in an orchestrated way into body tissues to target, and destroy, virus-infected or cancer cells. Destruction of these abnormal cells is achieved when they ingest cytotoxic enzymes (proteases) released by CTL. We propose that one of these cytotoxins, granzyme B, has a dual function, and that it is also involved in helping CTL to efficiently move towards the target cells by clearing a path through the local tissue structure.
Mechanism Of Breast Cancer Metastasis: Tumour Cell Remodelling Of The Extracellular Matrix
Funder
National Health and Medical Research Council
Funding Amount
$377,331.00
Summary
The main complication in breast cancers leading to death is metastatic relapse. This research aims to understand the role for a protease that promotes spread of breast cancer to the lymph nodes and lungs. The outcomes will identify a novel process that leads to lymph node metastasis and offer a new target for therapies that prevent relapse and tests to identify breast cancer patients at risk of relapse.
Migratory Behaviour And Cell Cycle Length Of Enteric Neuron Precursors
Funder
National Health and Medical Research Council
Funding Amount
$472,249.00
Summary
The activity of nerves in the intestine is essential for gastrointestinal function. Correct development of intestinal neurons requires migration of precursors to the correct location and control of proliferation to achieve correct neuron number. In this project we will identify the mechanisms regulating migration and proliferation of intestinal neuron precursors during normal development, and in mice with defects in intestinal neurons that are models of human motility disorders.
Effects Of Ischemia/ Reperfusion Injury On Enteric Neurons And Neuroprotective Strategies
Funder
National Health and Medical Research Council
Funding Amount
$566,277.00
Summary
The intestine can suffer restricted blood flow, creating a region of damaged or dead bowel. This leads to severe medical emergencies, complications and even death. Loss of blood flow and damage can be a serious complication for intestinal transplant surgery, which compromises patient survival and recovery. The project brings together transplant surgeons and basic scientists to solve problems caused by intestinal ischemia. A major result will be to improve outcomes for Australian patients
MECHANISMS OF MOTILITY AND METASTASIS In BREAST CANCER
Funder
National Health and Medical Research Council
Funding Amount
$209,505.00
Summary
The broad aim of this proposal is to elucidate novel molecular mechanisms of breast cancer cell motility that are relevant to metastasis or the spread of cancer. The function of two genes will be studied. We propose that (1) reduced on-random motile (ROM) regulates the speed of cancer cell movement, and (2) Neural Wiskott-Aldrich syndrome protein (N-WASP) regulates the directional component of cell movement. We will relate the function of ROM and N-WASP to rapid, linear walking along collagen fi ....The broad aim of this proposal is to elucidate novel molecular mechanisms of breast cancer cell motility that are relevant to metastasis or the spread of cancer. The function of two genes will be studied. We propose that (1) reduced on-random motile (ROM) regulates the speed of cancer cell movement, and (2) Neural Wiskott-Aldrich syndrome protein (N-WASP) regulates the directional component of cell movement. We will relate the function of ROM and N-WASP to rapid, linear walking along collagen fibres in live tumours and to breast cancer metastasis to the lung. ROM will be inhibited in breast cancer cells and we expect increases in both the speed of cell movement and metastasis. Therefore, ROM functions as a suppressor of metastasis. Inhibition of N-WASP, however, is expected to compromise both the directionality of cell movement and metastasis. N-WASP is therefore, a promoter of metastasis. At the completion of this work, the regulatory mechanisms of motility and metastasis by ROM and N-WASP will be defined. This will facilitate the development of biologically targeted agents for ROM and N-WASP that can be used to control metastasis. In addition, these agents that target the motility pathway are appropriate for use in combined therapy with agents that target a different pathway such as survival or growth. This will significantly improve disease control rates or the proportion of patients with partial or complete disease regression. This proposal addresses the National Health Priority, cancer, and related National Research Priority, ageing well and ageing productively, where in the longer term, we will be able to create new and much needed therapy for metastasis.Read moreRead less
The Role Of Actin-based Motility As A Virulence Mechanism And Potential As An Antiviral Target
Funder
National Health and Medical Research Council
Funding Amount
$325,798.00
Summary
Our repertoire of effective treatments for infectious diseases is fast becoming exhausted as resistance to antibiotics and antivirals evolves and rapidly spreads throughout our community. We have developed a new paradigm in treating viral diseases that we predict will not give rise to resistance, and this project will be the first to demonstrate the effectiveness of this novel therapy in an endemic disease model.
Role Of L1CAM In Enteric Nervous System Development
Funder
National Health and Medical Research Council
Funding Amount
$374,759.00
Summary
There are millions of nerve cells in the gut. During development, these nerve cells arise from cells (neural crest) that migrate from the developing brain. Neural crest cells migrate into and along the gut. Some humans have a condition called Hirschsprung's disease in which nerve cells are absent from parts of the gut. Afflicted individuals have severe constipation and require surgery. In this study, we will identify the mechanisms controlling neural crest migration in the developing gut.