Examining The Role Of ASIC Channels In Pain Through The Development Of Subtype-specific ASIC Channel Modulators.
Funder
National Health and Medical Research Council
Funding Amount
$617,256.00
Summary
Acid sensing ion channels (ASICs) sense changes in acidity in the body. They are found throughout the body and may underlie nerve damage in stroke and some types of pain. ASICs also have many as yet unknown functions. A lack of selective tools to study ASICs is a major barrier to a complete understanding of what they do. This proposal aims to modify three animal toxins which block these receptors to make useful tools to study their function, in particular their role in sensing pain.
Interaction Of TRP Channels And Inflammatory Mediators: A Critical Role In Visceral Pain
Funder
National Health and Medical Research Council
Funding Amount
$308,747.00
Summary
Transient receptor potential, or TRP channels, are involved in generating many of the sensations we feel, such as touch and pain. The function of these channels can be altered by substances released by the body during inflammation. Some TRP channels have specialized roles in signalling pain from the colon which can be enhanced during colonic inflammation. Understanding how TRP channels and inflammatory mediators function and interact is essential if we are to find treatments for colonic pain.
Mechanisms Controlling The Excitability Of Corneal Nociceptor Nerve Terminals
Funder
National Health and Medical Research Council
Funding Amount
$364,759.00
Summary
The project uses a new approach that allows, for the first time, electrical activity to be recorded and analysed from the very fine nerve endings of nerves whose activation results in painful sensations. Using this technique the mechanisms by which substances released in damaged and inflamed tissues lead to discharge of action potentials and the sensation of pain will be investigated. In particular the project investigates the role of a population of sodium ion selective pores (channels) that ar ....The project uses a new approach that allows, for the first time, electrical activity to be recorded and analysed from the very fine nerve endings of nerves whose activation results in painful sensations. Using this technique the mechanisms by which substances released in damaged and inflamed tissues lead to discharge of action potentials and the sensation of pain will be investigated. In particular the project investigates the role of a population of sodium ion selective pores (channels) that are uniquely expressed in pain sensing nerves. These channels have been hypothesised to play an important role in determining the behaviour of these nerves. In addition, the project investigates how some substances released in inflamed tissues sensitize pain sensing nerves, causing them to more readily discharge action potentials. This change is the major cause of pain associated with inflammatory diseases such as arthritis. In summary, the proposed project will provide new insight into how pain sensing nerves function. This knowledge is essential for the development of more effective strategies for treating pain resulting from inflamed and damaged tissue.Read moreRead less
Experimental Validation Of A Clinical Indicator Of Utricular Function.
Funder
National Health and Medical Research Council
Funding Amount
$198,689.00
Summary
The vestibular system is responsible for our sense of balance, it is located in the inner ear and is responsible for maintaining posture and helping an organism to make appropriate eye movements when the head moves. Damage to the vestibular system by disease or accident is extremely debilitating for a patient. A chief goal of our research program is to develop simple tests of the vestibular system that can be used in the clinic to diagnose vestibular disorders. Most present clinical tests only t ....The vestibular system is responsible for our sense of balance, it is located in the inner ear and is responsible for maintaining posture and helping an organism to make appropriate eye movements when the head moves. Damage to the vestibular system by disease or accident is extremely debilitating for a patient. A chief goal of our research program is to develop simple tests of the vestibular system that can be used in the clinic to diagnose vestibular disorders. Most present clinical tests only test the part of the vestibular system that responds to angular rotations (the semicircular canals). There are few good tests that can reliably diagnose problems concerned with sensed position (the otoliths). Recent evidence from human studies has shown that by delivering small electrical currents (galvanic stimulation) via electrodes located on the surface of the skin behind the ears, a characteristic pattern of eye movement occurs. Our hypothesis is that the distinctive pattern of eye movement produced is a result of otolith stimulation. The aim of this project is to determine exactly how these small currents produce the eye movements and if these eye movements are in fact mediated by the otoliths. To determine the physiology that underlies these types of responses we are unable to conduct these experiments in humans. Our present program will therefore use both behavioural and physiological experiments on guinea pigs to test our hypotheses about galvanic stimulation and otolith function. The significance of this work lies in that it will lead to a new way of evaluating the function of the gravity sensing part of the human vestibular system which appear to be uniquely important for patients with balance problems.Read moreRead less
Transient Receptor Potential Channels (TRPs) As Transducers And Targets In Primary Visceral Afferents
Funder
National Health and Medical Research Council
Funding Amount
$669,130.00
Summary
Transient receptor potential, or TRP channels, are involved in generating many of the sensations we perceive, such as heat, cold, touch and pain. Some TRP channels are specialized to signal pain from visceral organs, which we must investigate if we are to find treatments for visceral pain, which are currently lacking.
Lesions of the primary visual area (V1) are sufficient to cause blindness, even though there are many other brain areas normally involved in vision. However, when V1 is lesioned very early in life people show some recovery, and may be able to see well enough to perform everyday activities. In order to understand what happens in the brain that allows this preservation of vision, we will study changes in the pathways linking the eyes to the brain, following lesions at different ages.
One of the main trends in the evolution of the primate brain was the huge expansion of the cortical areas devoted to visual processing. However, the exact role of individual areas remains highly controversial, making detailed physiological and anatomical studies in suitable primate models a key step to elucidating their function in the human brain. We will address one particular aspect of this problem, namely the organisation of the cortical areas that provide visual control for skilled movement ....One of the main trends in the evolution of the primate brain was the huge expansion of the cortical areas devoted to visual processing. However, the exact role of individual areas remains highly controversial, making detailed physiological and anatomical studies in suitable primate models a key step to elucidating their function in the human brain. We will address one particular aspect of this problem, namely the organisation of the cortical areas that provide visual control for skilled movements. It is proposed that there are two parallel brain circuits involved in the analysis of motion, one tracking the movement of objects, and the other analysing a person s self-motion. Consider, for example, the task of a tennis player who has to return a serve. In order to achieve this, the brain must precisely integrate information about the ball s motion, as well as information about the player s speed and direction. This requires precise control of eye movements (to keep the eyes on the ball), as well as the ability to control the limb and trunk muscles. The aim of this study will be to map the anatomical framework underlying our ability to process all the relevant visual motion information, and to coordinate the appropriate motor responses. Such work is fundamental for understanding the functional organisation of the brain. It also has the potential to lay the groundwork for developments in areas of applied research, including medicine (e.g. the design of better rehabilitation strategies for people with brain damage), robotics- artificial intelligence (e.g. the improvement of artificial systems capable of vision), and the cognitive sciences (e.g. a better understanding of factors that limit human responses to visual stimuli).Read moreRead less
Over thirty different areas, comprising nearly half the primate cerebral cortex, are involved in processing visual information. From the anatomical viewpoint, each of these areas should be capable of receiving visual information independently, through parallel anatomical channels involving the brainstem. Yet, it has been observed that lesion of one particular area (the primary visual area, V1) results in loss of vision. This raises several questions. What type of visual information is carried by ....Over thirty different areas, comprising nearly half the primate cerebral cortex, are involved in processing visual information. From the anatomical viewpoint, each of these areas should be capable of receiving visual information independently, through parallel anatomical channels involving the brainstem. Yet, it has been observed that lesion of one particular area (the primary visual area, V1) results in loss of vision. This raises several questions. What type of visual information is carried by the parallel pathways to the other visual areas? Why aren t these other areas capable of sustaining vision without V1? Do V1 lesions trigger changes in the adult brain, which affect the other visual areas? As a step towards answering these questions, we will study the neural pathways that convey visual information directly to the middle temporal area (MT). MT is one of the best-characterised visual areas, and the anatomy of its neural inputs is well known, facilitating the interpretation of the results. We will investigate the type of visual information being sent to MT after lesions of V1, as well as the changes in the electrical responses of MT cells which result from this type of condition. This is a basic science study, the primary benefit of which will be advancement of knowledge on the mechanisms that underlie visual processing in normal and pathological situations. However, this type of work may also lay the groundwork for developments in areas of applied research. These may include medicine (e.g. the design of better rehabilitation strategies for people with brain damage), robotics- artificial intelligence (e.g. the development of more robust artificial systems capable of vision), and cognitive sciences (e.g. a better understanding of factors that limit human responses to visual stimuli).Read moreRead less
Behavioural And Physiological Tests Of Clinical Indicators Of Vestibular Function.
Funder
National Health and Medical Research Council
Funding Amount
$205,500.00
Summary
Part of the inner ear is responsible for our sense of balance and for maintaining clear vision and stable posture. Recurring vertigo attacks and persistent imbalance can disrupt the most productive years of patients' lives and balance-related falls account for more the half of accidental deaths in the elderly. Despite this most doctors find dizziness difficult to diagnose and impossible to treat, so specialist Balance Disorders Clinics see many patients a year but still have very long waiting ti ....Part of the inner ear is responsible for our sense of balance and for maintaining clear vision and stable posture. Recurring vertigo attacks and persistent imbalance can disrupt the most productive years of patients' lives and balance-related falls account for more the half of accidental deaths in the elderly. Despite this most doctors find dizziness difficult to diagnose and impossible to treat, so specialist Balance Disorders Clinics see many patients a year but still have very long waiting times. There is then clearly a major need to improve the understanding and the treatment of dizzy patients and improvement will come about through scientific understanding of vestibular dysfunction, and technological realization of improvements in the assessment and treatment of patients. This project seeks to identify whether 3 simple new indicators of balance function are valid, using tests on guinea pigs to understand the way in which they work.Read moreRead less
Oculomotor Tests Of Otolith Function Using Human Centrifugation
Funder
National Health and Medical Research Council
Funding Amount
$284,450.00
Summary
The effects of dysfunction of the balance system of the inner ear (the vestibular system) can range from mild brief episodes of dizziness to almost complete incapacitation: where the patient feels unstable, their posture is unstable, their vision is unstable. In order to guide appropriate treatment and rehabilitation, diagnostic tests are needed to identify whether the dysfunction is due to a brain problem or a problem in the inner ear, and if an ear problem - which part of the inner ear system ....The effects of dysfunction of the balance system of the inner ear (the vestibular system) can range from mild brief episodes of dizziness to almost complete incapacitation: where the patient feels unstable, their posture is unstable, their vision is unstable. In order to guide appropriate treatment and rehabilitation, diagnostic tests are needed to identify whether the dysfunction is due to a brain problem or a problem in the inner ear, and if an ear problem - which part of the inner ear system is affected. By combining basic research with clinically feasible methods my colleagues and I have, with NH and MRC support, developed some of the most widely used clinical tests of balance function available today (see Halmagyi, Cremer and Curthoys 2003 for a review). In this Project I seek to continue the development of a test of part of the balance system (the utricular macula) for which there are few acceptable tests. I will do that by using the unique facilities available at Sydney University and RPA Hospital, presenting controlled stimuli (linear accelerations) to healthy human subjects and patients with known vestibular losses, and measuring precisely their eye movement responses to these stimuli using computerized image processing techniques. The experiments will test an hypothesis about how part of the vestibular system, the utricular macula, works and controls eye movements. One eye movement response, rolling of the eye around the line of sight (called ocular torsion) during maintained roll head-tilts (to the patients left or right) may be due to the joint activation of two regions of the balance receptors: the utricular and saccular maculae. As a result of a recent direct test we have managed to conduct on two normal subjects, we think that hypothesis should be thoroughly re-tested on subjects and patients with known vestibular losses and in doing so provide new understanding of otolith function which may lead to new clinical tests.Read moreRead less