Regulation Of Myotubularin Function By The Novel 3-phosphatase Adapter Protein (3-PAP)
Funder
National Health and Medical Research Council
Funding Amount
$488,273.00
Summary
Phospholipids are important components of cell membranes. Phospholipids are turned-on by enzymes called kinases and these phospholipids stimulate a variety of critical functions within the cells. Phospholipids are turned-off by another type of enzymes classed as phosphatases, thereby switching off a broad range of cell functions. Myotubularin is an enzyme, which neutralizes particular type of phospholipids that are involved in the shuttling of proteins between compartments within the cell. Loss ....Phospholipids are important components of cell membranes. Phospholipids are turned-on by enzymes called kinases and these phospholipids stimulate a variety of critical functions within the cells. Phospholipids are turned-off by another type of enzymes classed as phosphatases, thereby switching off a broad range of cell functions. Myotubularin is an enzyme, which neutralizes particular type of phospholipids that are involved in the shuttling of proteins between compartments within the cell. Loss of function of myotubularin, due to inherited genetic changes (mutations), leads to abnormal muscle development manifesting as weakness since birth, and this particular disease is known as 'X-linked myotubular myopathy'. However, there is yet no information on the mechanisms by which failure of protein shuttling (transport) causes myopathy. We have discovered a new protein, 3-phosphatase adapter protein (3-PAP) that links with myotubularin and plays an important role in the function of myotubularin. Our research proposal seeks to clarify the important role of 3-PAP in the development of muscle cells. We propose to study the location of 3-PAP within cells and analyse the influence of 3-PAP on protein shuttling. We have created mice that are deficient in the 3-PAP gene. These special mice will help us understand the importance of 3-PAP in the development and function of nerve and muscle tissue.Read moreRead less
Delayed Neuronal Death After Peripheral Nerve And Spinal Cord Injury
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
After injury to the nervous system, even under optimal conditions for regeneration of broken nerve processes (axons), there is little chance of normal function being restored because few regrowing axons will find appropriate cells to connect with. The time taken for many regrowing axons to reach their targets can be so long that both the axons and their targets lose the ability to recognize each other. Equally importantly, some damaged nerve cells die over the months that follow an injury. This ....After injury to the nervous system, even under optimal conditions for regeneration of broken nerve processes (axons), there is little chance of normal function being restored because few regrowing axons will find appropriate cells to connect with. The time taken for many regrowing axons to reach their targets can be so long that both the axons and their targets lose the ability to recognize each other. Equally importantly, some damaged nerve cells die over the months that follow an injury. This slow loss of nerve cells can lead to progressive and ongoing deterioration. Given recent advances in our understanding of how to improve axon regeneration, the degree of functional recovery could be disappointing unless we know more about how to prevent these neurones from dying. This project will use rats as experimental animals to try to understand which types of nerve cells are likely to die or survive after injury to peripheral nerve trunks or to the spinal cord. We will investigate two regions of the nervous system that are commonly involved in injuries in people. After injuries to limb nerves, people lose sensation and movement and can unpredictably develop chronic conditions such as neuropathic pain (unrelated to the damage and often occurring spontaneously) as well as poor blood flow and wound healing in the hands-feet. After most injuries to the spinal cord, the lower part of the cord beyond the injury (in particular the lumbosacral cord controlling hindlimb movement and sensation and the function of bladder, bowel and sexual organs) is often disconnected from the brain leading to paralysis and disrupted control of pelvic organ function. We will identify and study specific populations of nerve cells with sensory (mainly pain-sensing) functions and four identified groups of nerve cells in the lumbosacral cord that project to the brain. Once we know which nerve cells do not survive, we will search for the likely causes of their death and ways to prevent it.Read moreRead less
The Mechansim Of Cachexia Induced By The TGF-b Superfamily Cytokine, MIC-1
Funder
National Health and Medical Research Council
Funding Amount
$544,200.00
Summary
MIC-1 is a protein first cloned and characterised by our research group. It belongs to the TGF beta protein superfamily which is very important in development of cancer, wound - fracture healing and inflammation. Recent evidence also suggests it can act as an appetite suppressant, and this is especially relevant in conditons like cancer where it is overproduced. This project seeks to understand the mechanisms for its capacity to modify appetite
The Role Of The NPY System In The Regulation Of Appetite And Satiety
Funder
National Health and Medical Research Council
Funding Amount
$1,088,384.00
Summary
Eating disorders that have a causative role in the development of obesity and anorexia present massive health care problems for which current preventive methods and therapies are unsatisfactory. The studies proposed here combine sophisticated molecular techniques with state-of-the-art biochemical and physiological analyses. By utilising a panel of unique mouse models (many of which are only available to us), missing or overproducing key factors in the regulation of appetite and satiety this rese ....Eating disorders that have a causative role in the development of obesity and anorexia present massive health care problems for which current preventive methods and therapies are unsatisfactory. The studies proposed here combine sophisticated molecular techniques with state-of-the-art biochemical and physiological analyses. By utilising a panel of unique mouse models (many of which are only available to us), missing or overproducing key factors in the regulation of appetite and satiety this research will make highly original and internationally competitive contributions to the understanding of these disorders. The results will have a significant impact on the development of novel diagnostics and potential treatments for obesity and anorexia. In addition, funding provided through this grant would not only help to find answers to these important questions but will also provide the basis for the generation of several novel mouse models. These animal models will also be beneficial tools for the wider scientific community here in Australia and worldwide. We have a proven record in the generation and comprehensive analysis of transgenic and knockout mice models making this proposal not only feasible but also highly likely to succeed and provide great new insight into extremely important health problems.Read moreRead less
An FMRI Analysis Of The Functional Organization Within The Brain Of Experimental Superficial And Deep Orofacial Pain
Funder
National Health and Medical Research Council
Funding Amount
$307,526.00
Summary
This project will investigate how the human brain processes a number of important aspects of human jaw muscle pain that are clinically relevant but poorly understood. For example, we do not understand why jaw muscle pain has such different behavioural effects to skin pain. Jaw muscle pain is associated with a significant emotional component not seen in with skin pains. Also, skin pain usually has a sharp or burning quality, is well-localized and is readily treated, while jaw muscle pain is a dee ....This project will investigate how the human brain processes a number of important aspects of human jaw muscle pain that are clinically relevant but poorly understood. For example, we do not understand why jaw muscle pain has such different behavioural effects to skin pain. Jaw muscle pain is associated with a significant emotional component not seen in with skin pains. Also, skin pain usually has a sharp or burning quality, is well-localized and is readily treated, while jaw muscle pain is a deep pain that has a dull, aching quality that may be referred to related sites of the face, head and neck. It is also not known why jaw muscle pain is more common in females in comparison to males. Chronic jaw muscle pain is a major symptom of patients with Temporomandibular Disorders, the most common form of non-dental orofacial pain and that involves pain in or about the jaw joint and-or jaw muscles, and often limitation of jaw movement. Chronic jaw muscle pain can have a severe effect on quality of life but its diagnosis and management is difficult. Despite the widespread prevalence of chronic orofacial pains, we have little information on the central processing of chronic human orofacial pain. This proposal will improve our fundamental understanding of how jaw muscle pain is processed in the brain. The way that the central nervous system processes and represents jaw muscle pain will help explain why these pains present differently in the clinic and should provide important information on the differences between females and males in the representation of jaw muscle pain. This information on the central processing of chronic orofacial pain is crucial to inform the direction of novel or specific management strategies. Our long-term goal is to improve the diagnosis and management of patients with Temporomandibular Disorders, and the present application represents a major new direction of research.Read moreRead less
Function Of The Lysophospholipid Receptor Family In Neuronal Stem Cells And Their Progenitors.
Funder
National Health and Medical Research Council
Funding Amount
$380,723.00
Summary
Stem cells have the potential to give rise to a vast array of differentiated cells. Neuronal stem cells (NSC) can differentiate into progenitor cells which can themselves differentiate into cells of the nervous system: neurons and macroglial cells (astrocytes, oligodendrocytes, Schwann cells). This in turn can assist in the treatment of degenerative diseases such as multiple sclerosis, Parkinson's disease, motoneuron desease etc. Our project aims to study the effects on NSC and their progenitor ....Stem cells have the potential to give rise to a vast array of differentiated cells. Neuronal stem cells (NSC) can differentiate into progenitor cells which can themselves differentiate into cells of the nervous system: neurons and macroglial cells (astrocytes, oligodendrocytes, Schwann cells). This in turn can assist in the treatment of degenerative diseases such as multiple sclerosis, Parkinson's disease, motoneuron desease etc. Our project aims to study the effects on NSC and their progenitor cells of the lysophospholipids lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), bioactive molecules known to play an essential role in the nervous system during development and inflammation. Our project aims to understand the mechanisms of action of these molecules in NSC maintenance, proliferation, differentiation and migration. By understanding how these molecules are able to regulate NSC biology will provide new avenues in the development of tools necessary for stem cell therapy.Read moreRead less
Functional Copper Deficiency Models Of Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$454,691.00
Summary
Alzheimer's disease is a serious neurodegenerative disease which increases in incidence with age. It affects the quality of life and care required for approximately 160,000 Australians and costs the national economy 6.6 billion dollars per annum. Current therapy is of limited efficacy. Our studies are directed towards testing the hypothesis that a functional deficiency of the essential trace element, copper, occurs in the brain with ageing, and this leads to oxidative stress and death of neurons ....Alzheimer's disease is a serious neurodegenerative disease which increases in incidence with age. It affects the quality of life and care required for approximately 160,000 Australians and costs the national economy 6.6 billion dollars per annum. Current therapy is of limited efficacy. Our studies are directed towards testing the hypothesis that a functional deficiency of the essential trace element, copper, occurs in the brain with ageing, and this leads to oxidative stress and death of neurons associated with Alzheimer's disease. We will use animal and cell culture models to test this hypothesis which is based on promising preliminary data from such models. We believe that beta amyloid, which accumulates in Alzheimer's brains and is believed to be a major part of the pathological mechanism, has a normal role in maintaining copper balance and that this balance is disturbed by ageing or particular mutations. This research should lead to better treatments using drugs which mobilise copper entry into cells.Read moreRead less
The Role Of Gonadotropins In Regulating The Production Of Alzheimer's Beta Amyloid
Funder
National Health and Medical Research Council
Funding Amount
$400,278.00
Summary
Currently, about 160,000 Australians suffer from dementia; of which 50-70% are Alzheimer's disease (AD) cases. AD is characterised clinically by memory and personality changes and pathologically by deposition of amyloid. Of particular importance in the disease pathogenesis, is a small molecule called beta amyloid, of which the overproduction is thought to be central to the development of AD. Changes in the levels of the reproductive hormones, particularly low levels of oestrogen during menopause ....Currently, about 160,000 Australians suffer from dementia; of which 50-70% are Alzheimer's disease (AD) cases. AD is characterised clinically by memory and personality changes and pathologically by deposition of amyloid. Of particular importance in the disease pathogenesis, is a small molecule called beta amyloid, of which the overproduction is thought to be central to the development of AD. Changes in the levels of the reproductive hormones, particularly low levels of oestrogen during menopause or testosterone during andropuase, has been associated with the increased risk of developing AD and in altering the levels of beta amyloid. Furthermore, menopause and andropause are also characterised by changes in other reproductive hormones such as the gonadotropins. High levels of the gonadotropins have also been associated with the increased risk of developing AD. Therefore it is important to identify how these changes modify the risk of developing AD. This study examines the role of the gonadotropins in regulating beta amyloid levels in cell culture and in an animal model for AD. Furthermore, this study will assess, in the animal model, the use of gonadotropin lowering agents to reduce levels of beta amyloid. The results from this study will provide important data on how reproductive hormones regulate beta amyloid. Further insight into these mechanisms will provide therapeutic or preventative strategies for AD.Read moreRead less
Adult Stem Cell Transplantation Therapy In Parkinsonian Rat
Funder
National Health and Medical Research Council
Funding Amount
$526,517.00
Summary
Parkinson's disease is a progressive neurodegenerative disorder characterised by slowness of movement, muscle rigidity and tremor. It affects about 1% of the population at age 50 and 10% over age 80. Symptoms are caused by low levels of dopamine, a chemical in the brain that helps control movement. The symptoms increase in severity with time, leading to increasing difficulty in walking, speaking, writing, swallowing and sleeping and increasing the incidence of broken bones from falls. Parkinson' ....Parkinson's disease is a progressive neurodegenerative disorder characterised by slowness of movement, muscle rigidity and tremor. It affects about 1% of the population at age 50 and 10% over age 80. Symptoms are caused by low levels of dopamine, a chemical in the brain that helps control movement. The symptoms increase in severity with time, leading to increasing difficulty in walking, speaking, writing, swallowing and sleeping and increasing the incidence of broken bones from falls. Parkinson's disease is incurable but the symptoms can be controlled with medications that replace the lost dopamine. Medications become less effective as the disease progresses and there is need for new therapies. Worldwide the hunt is on to discover new cell transplantation therapies to replace the dopamine in the brain and to prevent degeneration of the still surviving dopamine cells. Although embryonic stem cells might be useful for such therapies, they raise the risk of tumour formation from the transplanted cells. This aim of this proposal is to test, in parkinsonian rat, a therapy in which adult stem cells from the patient are transplanted into their own brain to provide a new source of dopamine. We have discovered a new and unique source of adult stem cells, the sense organ of smell in the nose. Small samples can be taken through the nose and we can grow these adult stem cells from people of all ages, including people with Parkinson's disease. As adult stem cells they avoid the ethical issues associated with embryonic stem cell transplantation and as cells from the same patient, they are not rejected by the immune system. This is being tested in principle by a world-first clinical trial in which we are taking another cell type from the nose, growing it in the lab, and transplanting into the injured spinal cord in a search for a cure for paraplegia. This project takes the first steps to developing a new treatment for Parkinson's disease using a patient's own adult stem cells.Read moreRead less
ROLE AND MECHANISM OF NADPH OXIDASE IN ISCHEMIC STROKE AND NEUROTRAUMA
Funder
National Health and Medical Research Council
Funding Amount
$619,015.00
Summary
Stroke is a leading cause of death. Despite many clinical trials there is only 1 approved drug for acute treatment but with a narrow time window t. Similarly, there is no therapy for traumatic brain injury (TBI). Patients often suffer from nuerological diasblity or die. This study tests whether free radicals either in nerve cells or blood vessels are the cause of brain damage and can be targeted for new therapies.