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Characterization Of Novel Regulators Of Erythropoiesis
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature fu ....Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature functional cells. We have identified six molecules which interact with Lyn in red blood cells. We have shown that amolecule called HS1 is important for epo function in individual red blood cells and now we plan to investigate its functions in whole animals, including mice that lack the HS1 gene. We have also shown that a molecule called Trip1 is important for red blood cell development. Interestingly, this molecule also interacts with the thyroid hormone receptor and can influence the effects of epo and thyroid hormone on red blood cell development. The interplay between these two hormones will be looked at in more detail both at the cell and whole animal levels in normal mice and those lacking the thyroid hormone receptor gene. The third Lyn binding molecule we isolated is a novel gene-we have named it ankyrin repeat protein in line with the molecules it is related to. This gene is expressed in red blood cells and we aim to investigate what role it plays in the development of these cells. The fourth gene is also novel and is closely related to another called AFAP-110, which can exert effects on the structure of a cell. Its role in red blood cell structure will also be investigated. Finally, the last two molecule we have identified are both novel and are unrelated to any other known proteins. As above, the effects of these two molecules on red blood cell development will be investigated.Read moreRead less
Ocular Motility In Autism And Asperger S Disorder: Dissociation Of Motor Deficits.
Funder
National Health and Medical Research Council
Funding Amount
$131,235.00
Summary
We will use ocular motor technology to investigate motor dysfunction in autism and Asperger's disorder, to advance our understanding of the neurobiological bases of these disorders. This will help clarify whether neural networks are differentially disrupted in these disorders, as our previous clinical research suggests. This dissociation and the subsequent development of an ocular motor clincal screen may improve diagnosis, and potentially treatment, of these devastating conditions.
Motor Functioning In Autism And Asperger's Disorder: Furthering Current Neurobehavioural And Clinical Definitions
Funder
National Health and Medical Research Council
Funding Amount
$354,932.00
Summary
While it is well known that autism and Asperger's disorder are associated with social, communicative, and behavioural symptoms, it is less well known that affected individuals also have considerable movement and coordination difficulties. For example, these children often have problems with hand writing, walking, hopping, skipping, catching, and running. These skills are very important for success at school; for example, if children are unable to participate in school sports they often feel isol ....While it is well known that autism and Asperger's disorder are associated with social, communicative, and behavioural symptoms, it is less well known that affected individuals also have considerable movement and coordination difficulties. For example, these children often have problems with hand writing, walking, hopping, skipping, catching, and running. These skills are very important for success at school; for example, if children are unable to participate in school sports they often feel isolated and rejected from the peer group. Also, hand writing problems have a significant impact on children's academic performance. Our previous research has suggested that there may be particular patterns of motor problems that characterise individuals with autism and Asperger's disorder. Our proposed research aims to use the kinds of 3D motion analysis technology used in the movie industry to capture exactly how people affected by these conditions move and respond to the environment. This study will enable us to highlight particular parts of the brain-motor circuitry that are affected by these disorders and will also enable us to more clearly distinguish how autism is different from Asperger's disorder. Ultimately, it is hoped that our motor investigations will lead to improved assessment and interventions for these disorders.Read moreRead less
Prevalence report by the Australian Advisory Board on Autism Spectrum Disorders (ASD) estimated that 1 child in every 160 children in the 6-12 year-old age group is affected by ASD. There is no cure for ASD and the causes are not understood. We propose that sex hormones may play a role in the development of these disorders. We will test this hypothesis using knockout and transgenic mouse models which have social interaction deficits and brain structure reminiscent of these disorders.
Using Epidemiology To Inform Psychiatric Classification (DSM-V And ICD-11)
Funder
National Health and Medical Research Council
Funding Amount
$631,502.00
Summary
Classification systems are vital for scientific progress. The classifications of mental disorders of the World Health Organization and the American Psychiatric Association are both being revised and this Australian team is a principal contributor to both processes. We have access to three national epidemiological surveys (n-30,000) that will inform fundamental issues by developing models of mental disorder typology and identifying practical improvements in the classification systems.
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
Early Detection Of Infants And Young Children With Autism
Funder
National Health and Medical Research Council
Funding Amount
$268,250.00
Summary
Autism is a severely handicapping condition adversely affecting social interaction, communication, behaviour, interests, and activities. Autism requires treatment at an early age (before 4 years). Despite finding that parents notice problems with their child's development within the first 2 years, on average diagnoses are made around 6 years of age. Treatment for autism should begin as early as possible to improve outcome. Diagnosis requires specialist assessment and these services are limited. ....Autism is a severely handicapping condition adversely affecting social interaction, communication, behaviour, interests, and activities. Autism requires treatment at an early age (before 4 years). Despite finding that parents notice problems with their child's development within the first 2 years, on average diagnoses are made around 6 years of age. Treatment for autism should begin as early as possible to improve outcome. Diagnosis requires specialist assessment and these services are limited. Therefore it is not possible to undertake such assessments with all children who have developmental problems. This project therefore proposes to evaluate a method for screening large populations of children for autism, thus enabling timely and more appropriate referral to assessment services. Previous work by the investigators has developed a potential screening tool (DBC Early Screen) for autism in young children under 4 years with developmental delay that has high levels of accuracy in identifying those infants and children who are at risk of autism and require specialist assessment. This project proposes to undertake a community field trial to assess the accuracy and reliability of this early screen and to establish its suitability for wide use as a population screening tool. The preliminary testing of DBC Early Screen demonstrated that a community field trial was feasible. The results of this study will facilitate the referral of infants and young children to specialist autism assessment services, thus enabling the commencement of appropriate early intervention for children and their families from an early age.Read moreRead less
An Examination Of Motor Functioning In Autism And Asperger's Disorder: An Analysis Of Gait & Cortical Brain Activity.
Funder
National Health and Medical Research Council
Funding Amount
$120,220.00
Summary
Autism is a developmental disorder characterised by a triad of deficits: delayed and atypical language development, impaired development of social skills, and ritualistic and stereotypic behaviour. Although not part of the standard diagnosis, movement disorders and gait abnormalities have been clinically observed in autism similar to those seen in Parkinson's disease. In addition, individuals with Asperger's disorder may appear more clumsy, have a stiff or awkward way of walking, and exhibit poo ....Autism is a developmental disorder characterised by a triad of deficits: delayed and atypical language development, impaired development of social skills, and ritualistic and stereotypic behaviour. Although not part of the standard diagnosis, movement disorders and gait abnormalities have been clinically observed in autism similar to those seen in Parkinson's disease. In addition, individuals with Asperger's disorder may appear more clumsy, have a stiff or awkward way of walking, and exhibit poor coordination in posture and gesture. It has been suggested that there is disruption within the basal-ganglia-thalamocortical circuitry (the region connecting the frontal and sub-cortical structures), which may cause the motor dysfunction seen in autism and Asperger's disorder. Few studies have attempted to isolate particular stages of motor functioning which may account for the coordination and motor delay observed clinically in autism and Asperger's disorder. A recent study of ours found evidence to suggest that motor planning deficiencies may account for the 'clumsy' movement patterns frequently reported in the autism - Asperger's disorder literature. Therefore, the aim of this research is to provide a comprehensive neurobehavioural and neurophysiological analysis of motor functioning in young people with autism and Asperger's disorder to further examine the exact stages of motor processing which are deficient in these disorder groups. Recent retrospective studies have shown that even as infants children with autism exhibit clear features of motor disturbance, which, if detected and clearly defined, could advance early diagnosis. In addition to advancing the clinical definition of autism and Asperger's disorder, a careful examination of motor disturbance may also illuminate the neurobiological underpinnings of these disorders.Read moreRead less
THE EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION (TMS) ON RAT MODELS OF DEPRESSION
Funder
National Health and Medical Research Council
Funding Amount
$204,274.00
Summary
Repetitive Transcranial Magnetic Stimulation (rTMS) is the direct stimulation of the brain by using high field magnetic pulses. It is a new technique that has been demonstrated to have some potential as a treatment of depressive illness and possibly other neuropsychiatric disorders. At this early stage of its investigation, the parameters of stimulation that are most likely to be therapeutic, and its mechanisms of action, are not known. Published studies vary in the frequency, duration and exten ....Repetitive Transcranial Magnetic Stimulation (rTMS) is the direct stimulation of the brain by using high field magnetic pulses. It is a new technique that has been demonstrated to have some potential as a treatment of depressive illness and possibly other neuropsychiatric disorders. At this early stage of its investigation, the parameters of stimulation that are most likely to be therapeutic, and its mechanisms of action, are not known. Published studies vary in the frequency, duration and extent of stimulation, with no firm guidelines about optimal parameters. Empirical study of the relative effects of stimulation at different frequencies, at different numbers of stimuli and for different durations is therefore important for the future development of this treatment. Such an investigation is best carried out in an animal model of depression for both ethical and practical reasons, as such studies in patients would possibly take many years and be extremely difficult to conduct. We propose such a study in rat models of depression which have demonstrated validity and utility in drug research. Rat models have a long track record in developing psychiatric treatments and are cost-effective and of proven value. We also plan to investigate the neuroanatomy of the immediate-early genes induced by TMS and compare it with electroconvulsive shock (ECS) and a tricyclic antidepressant, two established treatments of depression. The results will have implications for future human studies in guiding us toward the optimal parameters for therapeutic effects. They will also enhance our understanding of the mechanism of action of TMS in depression.Read moreRead less
Therapeutic Implications Of A Molecular Link Between Survivin And Telomerase Reverse Transcriptase
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
A unifying feature of all types of cancer cells is that they are immortal. Our investigations will build upon our recent results that showed the gene survivin is involved in cancer cell immortalisation. We will characterise a molecular link between survivin and the enzyme telomerase, which is central to cancer cell immortality. Furthermore, we will demonstrate the therapeutic potential of turning off both survivin and telomerase as a novel approach to halting the growth of cancer cells.