Combined linear and angular head movements are integral components of our natural head movements. The vestibular sensory apparatus in the labyrinth of the inner ear, which comprises three semicircular canals and two otoliths acts as an inertial guidance system during head motion. The vestibular sensors mediate the angular and linear vestibulo-ocular reflexive eye movements imperative to stabilise vision during the head motions. However, it is unclear how these responses to sudden linear and angu ....Combined linear and angular head movements are integral components of our natural head movements. The vestibular sensory apparatus in the labyrinth of the inner ear, which comprises three semicircular canals and two otoliths acts as an inertial guidance system during head motion. The vestibular sensors mediate the angular and linear vestibulo-ocular reflexive eye movements imperative to stabilise vision during the head motions. However, it is unclear how these responses to sudden linear and angular motion in three dimensions are combined and processed. Diseases of the inner ear can produce incapacitating visual and balance disturbances, yet the normal function of some of the inner ears receptors, in particular the otoliths, cannot be easily tested. Clinical evidence has shown that patients with incapacitating attacks of vertigo can have impairment of either or both the semicircular canals and the otoliths. The aim of this project is to measure quantitatively the semicircular canal-otolith response to transient, high-acceleration combined linear-angular head movements to find a reliable way to test the otolith function. Based on physiological principles and my preliminary experiment, we plan to use an off-axis head rotation procedure, a three-dimensional eye movement recordings and vector analysis technique to assess the linear and angular vestibulo-ocular reflex response from the otoliths and semicircular canals in the labyrinth. The practical significance of answers to these questions is that they will characterise the combined linear and angular vestibulo-ocular reflex responses that stabilise vision during transient head movements. It will provide us with a greater understanding of the visual disturbance that patients experienced during these kinds of head movements following vestibular disease or surgery. Measurement of the linear vestibulo-ocular reflex may also provide a diagnostic test of otolith function clinically in disease states.Read moreRead less
Intracellular Survival Of Burkholderia Pseudomallei And Evasion Of Autophagy
Funder
National Health and Medical Research Council
Funding Amount
$450,799.00
Summary
Melioidosis is a disease with high mortality that is caused by the bacterium Burkholderia pseudomallei. Autophagy is a natural part of the mammalian immune system. This project seeks to explain how Burkholderia pseudomallei avoids killing by host autophagy and identify the bacterial factors necessary for its survival within cells. The identified genes will be future targets for medical intervention.
Depression, Anxiety And Somatic Distress: Syndromal Structure And Relationship To Onset Of Clinical Disorder
Funder
National Health and Medical Research Council
Funding Amount
$224,085.00
Summary
The project aims to identify the principal dimensions or syndromes underlying symptoms of psychological distress (negative emotional states such as depression, anxiety, stress and fatigue). We plan to use an intensive longitudinal design to examine how these syndromes develop into episodes of clinical disorder. We expect that episodes of disorder will be predicted not only by closely related syndromes, but also by other causally related syndromes - for example, a period of increased anxiety and ....The project aims to identify the principal dimensions or syndromes underlying symptoms of psychological distress (negative emotional states such as depression, anxiety, stress and fatigue). We plan to use an intensive longitudinal design to examine how these syndromes develop into episodes of clinical disorder. We expect that episodes of disorder will be predicted not only by closely related syndromes, but also by other causally related syndromes - for example, a period of increased anxiety and stress may precipitate a depressive disorder. This information is important for understanding the aetiology of clinical disorders, for refining diagnostic criteria, and for the prediction and prevention of disorder. We also plan to collect information about the degree of disability that people suffer and the type of health services they access at various levels of severity of each syndrome. We expect that subclinical levels of some syndromes will be associated with substantial impairment and service usage, but that for other syndromes impairment will be minimal until clinical levels of severity are reached. This information will give a more complete picture of the community-wide burden of emotional distress, and will be directly relevant to health planning and policy.Read moreRead less
The 3-dimensional Structure Of Anticancer Drug-DNA Complexes Determined By X-ray Crystallography
Funder
National Health and Medical Research Council
Funding Amount
$264,358.00
Summary
Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents ....Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents act by poisoning the DNA binding enzyme topoisomerase. Crystallographic analysis will give us unequivocal answers at the atomic level as to the exact way in which the drug binds to DNA and how this binding differs between antitumour active and inactive compounds. We believe that a knowledge of the DNA binding mode of a class of intercalating anticancer drugs at the atomic level is valuable in guiding drug design within that class.Read moreRead less
The Structural Basis For The Action Of Anticancer DNA-intercalating Topoisomerase Poisons
Funder
National Health and Medical Research Council
Funding Amount
$459,750.00
Summary
Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs ....Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs. Many of these drugs work by binding directly to DNA and poisoning the DNA-manipulating enzyme, topoisomerase. Our objective is to discover the molecular basis of how anticancer drugs act through their interaction with DNA and topoisomerase. We propose to use the successful X-ray crystallography methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of anti-tumour active drugs, to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. Crystallographic analysis provides unequivocal data, at near atomic resolution, of the nature of the molecular interactions which provide specificity and selectivity in drug-DNA complexes. This information will be a valuable guide in the further development of this important class of topoisomerase poisons as anticancer drugs. We will initiate structural studies of ternary complexes between the topoisomerase enzyme, DNA and anticancer drugs. The solution of the X-ray crystal structures of these ternary complexes will allow the design of new antitumour topoisomerase poisons to be put on a completely rational basis.Read moreRead less
Development Of A New Surgical-guidance Tool For Intra-operative Tumour Margin Assessment In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$557,982.00
Summary
One third of breast cancer patients undergoing breast conserving surgery have insufficient tissue removed, resulting in an increased risk of recurrence. We have developed a high resolution optical imaging probe with the potential to detect small areas of cancer. It could be used to help guide the surgeon to remove all cancerous tissue from the patient. This grant will allow us to develop the probe to a stage that it can be used during surgery, and perform the world’s first clinical scans.
Development Of Microscope-in-a-needle Devices For Improved Clinical Diagnostics
Funder
National Health and Medical Research Council
Funding Amount
$327,746.00
Summary
We have developed a new high-resolution optical imaging technology. The unique aspect of our research has been to redesign the imaging probe, miniaturising it to a few hundred microns in diameter, and encase it in a hypodermic needle – a ‘microscope-in-a-needle’. We are developing specific imaging probes to aid in the assessment of lung disease; the diagnosis of liver disease; and integrated into a brain biopsy needle to enable safer brain biopsies.
Advances in positron emission tomography now allow specific pathological features of many brain diseases such as Alzheimer's disease to be measured with a brain scan during life. This Fellowship will assist Professor Rowe and his team in their world leading work on new PET scanning techniques to improve diagnosis and assist the development of treatment for Alzheimer's and other degenerative diseases of the brain.
Improving Human FMRI Through Modeling And Imaging Microvascular Dynamics
Funder
National Health and Medical Research Council
Funding Amount
$486,144.00
Summary
In this project we aim to establish a reliable vascular baseline to improve mapping of both small-scale functional architecture and large-scale brain networks in functional human brain mapping using MRI. By mapping the grey matter vasculature with high detail in both humans and animals, and by computing and matching of these atlases across species we will be able to validate this approach in vivo to confirm the better spatial specificity of the newly developed approach.