Inner Ear Protein Function Studied Using RNA Interference
Funder
National Health and Medical Research Council
Funding Amount
$365,230.00
Summary
The proper functioning of all cells tissues and organs depends on specific proteins that are manufactured by readout from the genome. The inner ear is no exception to this general principle and hence the normal hearing process depends critically on the proper functioning of key proteins. However, because of inherent limitations in the methods used to study their function in living tissues, the precise role of many inner ear proteins in the complex hearing process is not known or is at best poorl ....The proper functioning of all cells tissues and organs depends on specific proteins that are manufactured by readout from the genome. The inner ear is no exception to this general principle and hence the normal hearing process depends critically on the proper functioning of key proteins. However, because of inherent limitations in the methods used to study their function in living tissues, the precise role of many inner ear proteins in the complex hearing process is not known or is at best poorly understood. In this project we will use a recently developed technique called RNA interference, to reduce the amounts of specific targeted proteins in the inner ear of experimental animals. We will then study the effects on the inner ear's ability to detect sounds. The technique differs from other genome-manipulating methods because it can be applied to a single intact organ in the mature animal. The results of this project will illuminate the role of specific inner ear proteins in the process of sound detection. The project will also demonstrate the feasibility of using the RNA interference technique to modify function in the adult inner ear, thus paving the way for future therapies for inherited hearing disorders.Read moreRead less
Obesity is a looming health crisis for Australians; it increases the chances of many serious diseases including diabetes, cancer, stroke and heart disease. Obesity occurs when the amount of energy consumed in food is greater than the energy used over an extended period. Because human beings usually get most of their food in a few meals each day, the size of those meals is very important. Deciding when to stop eating can exert a powerful control on energy intake. It is well known that nutrients r ....Obesity is a looming health crisis for Australians; it increases the chances of many serious diseases including diabetes, cancer, stroke and heart disease. Obesity occurs when the amount of energy consumed in food is greater than the energy used over an extended period. Because human beings usually get most of their food in a few meals each day, the size of those meals is very important. Deciding when to stop eating can exert a powerful control on energy intake. It is well known that nutrients reaching the gut cause the release of hormones from cells in the lining of the stomach and intestine. These hormones tell the brain when enough food has been consumed. It used to be thought that the hormones travelled in the blood stream to affect the brain directly. Recently, it has become clear that much of their effect is actually carried by sensory neurons with endings in the lining of the gut. The hormones have a powerful effect the sensory nerve fibres which then send electrical signals in nerve fibres running in the vagus nerve to the brain. Here they make connections which eventually influence the centres that control feeding. There is much to understand about how hormones affect the sensory nerve endings in the wall of the gut, whether all nerve fibres are affected the same way and what sort of information is conveyed to the brain. This project will use electrophysiological methods to identify which nerve fibres are activated by hormones, whether different hormones affect different nerve fibres, which nutrients activate particular nerve fibres and whether nerve fibres make selective contacts with particular hormone-releasing cells. These questions are important for understanding how we normally stop feeding and how drugs might be designed to cause feelings of fullness earlier in each meal.Read moreRead less
Sensory Innervation Of The Anal Region In Normal And Diabetic Guinea Pigs
Funder
National Health and Medical Research Council
Funding Amount
$372,389.00
Summary
Until something goes wrong, we take it for granted that we can empty our bowels on a regular basis, at a time and place of our choosing. Failure to achieve this is very distressing and substantially diminishes quality of life, if it occurs regularly. Disordered defecation, fecal incontinence and constipation are surprisingly common and their prevalence will continue to increase as our population ages and the incidence of diseases such as diabetes increases. In many people suffering these problem ....Until something goes wrong, we take it for granted that we can empty our bowels on a regular basis, at a time and place of our choosing. Failure to achieve this is very distressing and substantially diminishes quality of life, if it occurs regularly. Disordered defecation, fecal incontinence and constipation are surprisingly common and their prevalence will continue to increase as our population ages and the incidence of diseases such as diabetes increases. In many people suffering these problems, there is a detectable dysfunction of the sensory nerves in the anal region. These nerves supply information from the anal region to the spinal cord that can cause us to sense activity in our lower bowel and initiate defecation reflexes. These sensory pathways are important for clinical gastroenterology, but remarkably little is known about them. We are now able to investigate what it is the sensory nerves in the anal region sense, what they look like and where they go to in the spinal cord - in a single project. To do this we will use simple, but novel techniques that have been developed in this laboratory in an animal model. Once we know this, we will compare the function of sensory nerves in the anal region in diabetic animals with normal animals. This will give us insight into the role of sensory nerves in the development of fecal incontinence an unpleasant symptom for many people suffering advanced diabetes. My systematic approach will provide understanding of the basic cellular mechanisms and nerve pathways that underlie sensation in the anal region, helping both clinicians and patients understand the cause of defecatory disorders and potentially pointing the way to new therapies and strategies for diagnosis.Read moreRead less
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.
Mechanisms Underlying Disordered Skin Blood Flow Following Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$408,000.00
Summary
Many people who recover from traumatic injury or who have chronic conditions such as diabetes or neuropathy from exposure to a toxic chemical suffer from peripheral vascular disorders leading to poor circulation in the extremities. These conditions are characterised by impaired wound healing, cold hands and feet and ongoing pain. These people must face a long life with progressively increasing disability. Even normal ageing can lead to similar problems. This project is directed at understanding ....Many people who recover from traumatic injury or who have chronic conditions such as diabetes or neuropathy from exposure to a toxic chemical suffer from peripheral vascular disorders leading to poor circulation in the extremities. These conditions are characterised by impaired wound healing, cold hands and feet and ongoing pain. These people must face a long life with progressively increasing disability. Even normal ageing can lead to similar problems. This project is directed at understanding the role of the nerve supply to blood vessels in the skin in these disorders. The experiments will be conducted in skin blood vessels of rats with various forms of nerve lesion that will mimic these conditions in patients. We will use our knowledge of the structure and behaviour of nerve-blood vessel connections to analyse the changes in the properties of vascular smooth muscle and relate it to the state of the innervation. Skin arteries normally receive two types of nerve - sympathetic (which release noradrenaline) and afferent ( which release peptides) - that have opposing actions on the vessel (constriction and dilation respectively). We hypothesize that removal of part or all of the innervation changes the contractile mechanism of the smooth muscle in the wall of the vessel so that it becomes much more sensitive to calcium ions and produces larger and more prolonged contractions. We will combine electrophysiology and contraction studies with immunohistochemistry and biochemical analysis to define the relation between the nerve deficit and the vascular responses. The aim is to identify appropriate drug targets for which local application in the affected region can alleviate the symptoms without causing widespread side effects.Read moreRead less
Involvement Of Adrenergic Receptors In Neuropathic Pain
Funder
National Health and Medical Research Council
Funding Amount
$345,473.00
Summary
After nerve or tissue injury including burns, some people will suffer from a condition called neuropathic pain. This is a condition where chronic pain is endured, often totally unrelated to the initial injury or induced by events that would normally not be painful. Our project will determine whether this abnormal pain response is due to an abnormal communication between the nerves that carry pain signals (sensory nerves) and nerves that form part of the sympathetic nervous system, which is part ....After nerve or tissue injury including burns, some people will suffer from a condition called neuropathic pain. This is a condition where chronic pain is endured, often totally unrelated to the initial injury or induced by events that would normally not be painful. Our project will determine whether this abnormal pain response is due to an abnormal communication between the nerves that carry pain signals (sensory nerves) and nerves that form part of the sympathetic nervous system, which is part of autonomic (or involuntary) nervous system. We believe that this abnormal communication is due to an increase in the expression of special receptors called adrenergic receptors, on the sensory nerves. Our project will look at these receptors in the skin of animals that have had pain conditions induced, and also in skin samples from patients who suffer from neuropathic pain that can be classified as sensitive to sympathetic stimulation. By better understanding how neuropathic pain is derived, we can open the door to novel treatment approaches in these difficult to treat conditions.Read moreRead less
Discovering Genes For X-linked Charcot-Marie-Tooth Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$486,789.00
Summary
Our goal is to explore peripheral nerve degeneration by identifying the genes causing X-linked forms of Charcot-Marie-Tooth neuropathy. Using bioinformatic resources, next generation sequencing and state of-the-art microarray and mutation scannning technologies we will perform comprehensive systematic analysis of candidate genes on the X chromosome. Discovery of genes for this subset of inherited peripheral neuropathies will elucidate mechanisms causing neurodegeneration and lead to targeted the ....Our goal is to explore peripheral nerve degeneration by identifying the genes causing X-linked forms of Charcot-Marie-Tooth neuropathy. Using bioinformatic resources, next generation sequencing and state of-the-art microarray and mutation scannning technologies we will perform comprehensive systematic analysis of candidate genes on the X chromosome. Discovery of genes for this subset of inherited peripheral neuropathies will elucidate mechanisms causing neurodegeneration and lead to targeted therapeutic treatment strategies.Read moreRead less