Identification Of Novel Mechanisms Governing Stage-specific Regulation Of The Human Globin Genes
Funder
National Health and Medical Research Council
Funding Amount
$481,826.00
Summary
Hemoglobin is the major protein in red blood cells and is essential for the transport of oxygen from the lungs to the tissues. The disorders of hemoglobin production are the commonest genetic diseases worldwide. These diseases can be markedly improved with elevation of the form of hemoglobin produced by the developing embryo, fetal hemoglobin. We have identified key factors important for fetal gene expression. Our goal is to translate these findings into therapies for the hemoglobin disorders.
Body Segment Identity Specification By The Transcription Regulator, Moz
Funder
National Health and Medical Research Council
Funding Amount
$366,301.00
Summary
One in 28 newborns have birth defects. Cleft palate and aortic arch defects are among the most common, always requiring surgery and often causing lethality. We propose to study a protein, Moz, which is essential for palate and aortic arch development. Moz (Monocytic leukaemia zinc finger protein) was first identified in human chromosomal abnormalities causing particularly aggressive forms of childhood and adult leukaemia. We have shown previously that Moz is essential for the formation of blood ....One in 28 newborns have birth defects. Cleft palate and aortic arch defects are among the most common, always requiring surgery and often causing lethality. We propose to study a protein, Moz, which is essential for palate and aortic arch development. Moz (Monocytic leukaemia zinc finger protein) was first identified in human chromosomal abnormalities causing particularly aggressive forms of childhood and adult leukaemia. We have shown previously that Moz is essential for the formation of blood stem cells. Moz can regulate the activity of genes, but which genes it regulates in vivo is unknown. In the absence of Moz, mice are born with a cleft palate, lack the thymus, where immune cells are instructed, and fail to form the lung blood circulation, so that they are unable to supply their blood with oxygen after birth. Moz deficiency also causes defects of the vertebrate column, such that individual vertebrae acquire the appearance of their neighbours. These symptoms are typical for a general defect in positional information of individual body segments with respect to their location along the body axis. We will investigate the molecular mechanisms that require Moz in patterning of the body axis. This project will characterize a genetic mechanism that is crucial for normal development of the palate, the aorta and the vertebrate column.Read moreRead less
The Embryological And Molecular Basis Of Zic2 Involvement In Holoprosencephaly
Funder
National Health and Medical Research Council
Funding Amount
$624,145.00
Summary
The brain is the most complex organ in the human body and diseases or disorders of the brain can become evident at any stage of life. Generally such problems have profound consequnces for the affected individuals and their families. One of the most common problems of brain development that is evident either at birth or within the first years of life is called holoprosencephaly (HPE). This condition affects the midline of the brain and the face and can lead to delay in mental, motor and language ....The brain is the most complex organ in the human body and diseases or disorders of the brain can become evident at any stage of life. Generally such problems have profound consequnces for the affected individuals and their families. One of the most common problems of brain development that is evident either at birth or within the first years of life is called holoprosencephaly (HPE). This condition affects the midline of the brain and the face and can lead to delay in mental, motor and language development, seizures, and obvious facial abnormalities. In its most severe form only one eye develops in the middle of the face, a condition known as cyclopia and a large majority of the severely affected children will die late in gestation or at birth. This condition can be inherited, but because the genetic lesions that cause this problem affect different people differently, people can carry the causative genetic change(s) without knowing it. We need to identify and study the genetic lesions that contribute to this condition in order to begin to understand how we can stop these mutations affecting the developing foetus. Because it is difficult to study embryonic development in humans we have generated a mouse model of this condition. In the mouse model just one gene (called Zic2) is altered and embryos that have two copies of this alteration develop the most severe form of cyclopia and die in the second half of gestation. This means that the normal role of this gene is to stop us developing HPE. We will use this mouse model to see just when and how the Zic2 gene prevents HPE. In addition, we will look to see what other genes Zic2 interacts with by breeding mice that carry the mutation in Zic2 with mice that carry a mutation in a second gene that can also cause HPE. These experiments are very important because if we understand how Zic2 and other genes protect us from HPE we can begin to design strategies to decrease the risk of a child developing this condition.Read moreRead less
Foetal Determinants Of Sleep Disordered Breathing In Infants
Funder
National Health and Medical Research Council
Funding Amount
$174,691.00
Summary
Obstructive sleep apnea (OSA) has been identified and recorded in infants, however the factors that lead to the development of OSA and its prevalence in infants is unknown. We have recorded OSA in some infants and we demonstrated that the severity of apnea was at its peak at approximately 2 months of age and then resolved by 1 year. We hypothesised that these infants possibly had a maturational delay of breathing control during sleep. This project is designed to examine the development and preva ....Obstructive sleep apnea (OSA) has been identified and recorded in infants, however the factors that lead to the development of OSA and its prevalence in infants is unknown. We have recorded OSA in some infants and we demonstrated that the severity of apnea was at its peak at approximately 2 months of age and then resolved by 1 year. We hypothesised that these infants possibly had a maturational delay of breathing control during sleep. This project is designed to examine the development and prevalence of sleep and breathing disorders in infants. The prenatal factors that possibly influence development of sleep and breathing disorders in infants, in particular, the effects of maternal smoking will be determined. Pregnant women will be recruited for the study during their third trimester. The foetal movements, foetal breathing movements, heart rate and sleep state will be monitored continuously overnight in the patients home between 32 and 36 weeks gestation using a newly developed foetal movement monitor. The infants will be subsequently studied using overnight polysomnography at 2 months of age to assess their breathing, sleep patterns, arousal behaviour, and the presence and severity of central and obstructive apnea. A group from these infants will be selected and studied longitudinally to examine the development of sleep and breathing disorders more closely. These infants will undergo overnight sleep studies during the first week of life, then at 2 and 6 months of age. A detailed medical history will also be collected regarding the pregnancy, the perinatal history of the infant, exposure to cigarette smoke during pregnancy and postnatally, and the medical history of other family members. We will examine the quality and quantity of foetal movements and its association with the development of OSA. The occurrence of sleep and breathing disorders in the infants will be correlated with the foetal behaviour and, the prenatal and postnatal factors.Read moreRead less
What shapes our brain? This project aims to improve our fundamental understanding of the biological mechanisms that drive folding of the cerebral cortex, which occurs during development of the brain. Cortical folding is unique to humans and higher mammals, and is thought to underpin the emergence of intelligence and contribute to higher-order brain functions. This project will enhance knowledge of how the cerebral cortex folds and develop novel tools for analysing brain development. The project ....What shapes our brain? This project aims to improve our fundamental understanding of the biological mechanisms that drive folding of the cerebral cortex, which occurs during development of the brain. Cortical folding is unique to humans and higher mammals, and is thought to underpin the emergence of intelligence and contribute to higher-order brain functions. This project will enhance knowledge of how the cerebral cortex folds and develop novel tools for analysing brain development. The project will provide significant benefits including the generation of fundamental knowledge with implications for future understanding of cortical folding abnormalities in babies born preterm, following fetal growth retardation in utero, or when exposed to maternal alcohol. In the longer term, the project will contribute to improvements to human neurodevelopment and brain health.Read moreRead less
Role Of The Thymus In T Cell Homeostasis During Foetal And Postnatal Life In Sheep
Funder
National Health and Medical Research Council
Funding Amount
$264,750.00
Summary
The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cells, has considerable implications for the development of a pool of T cells able to respond to a large number of infections. Recent thymic emigrants represent a wide diversity of positively selected thymocytes exhibiting newly arising T cell specificities, but mature T cell pool e ....The mature T cell pool can arise from only two sources, either thymic export or expansion of the peripheral T cell pool or a mixture of both. The lifespan of either cell type, i.e. recent thymic emigrants or mature T cells, has considerable implications for the development of a pool of T cells able to respond to a large number of infections. Recent thymic emigrants represent a wide diversity of positively selected thymocytes exhibiting newly arising T cell specificities, but mature T cell pool expansion results in reduced diversity because of a predominant expansion of a limited number of clones. It follows that a mixing of the pool of older mature T cells with new ones just released from the thymus will introduce more variability, and hence greater adaptability into the immune system. We have developed techniques for labeling the thymus in vivo and the entire blood leukocyte pool in vivo using the long-term lymphocyte tracking dye CFSE. We can establish a cohort of labeled cells and we can, for the first time in any experimental system, track directly the survival, death or division of recent thymic emigrants and mature cells and their progeny together with their tissue homing properties and surface markers for periods of many months. This will enable us to determine the way in which the pool of mature T cells is built up during the formation of the foetal immune system and the way the mature T cell population is established and maintained in postnatal life.Read moreRead less
Early Origins, Progression And Aetiology Of Obesity, Metabolic Syndrome And Diabetes: A 30 Years Follow-up Study
Funder
National Health and Medical Research Council
Funding Amount
$1,194,979.00
Summary
This research proposal aims to use the unique existing Mater University Study of Pregnancy (MUSP) and its offspring data and conduct a 30-year follow-up of MUSP children to investigate the early origins, progression and causal pathways of obesity, metabolic syndrome and diabetes for young Australian. Findings of this study will extend our understanding of the factors driving these health problems with the ultimate aim of being able to reverse the obesity epidemic and improve public health.
Neural migration: Which cells advance and which stay behind? This project aims to examine the neural crest cells that colonise the developing gut and to identify why some cells advance while others stay behind to populate a region. Directed cell migration is essential for normal development, including for the nervous system. In most of the migratory cell populations that have been analysed to date, all of the cells migrate as a collective from one location to another. However, there are also mi ....Neural migration: Which cells advance and which stay behind? This project aims to examine the neural crest cells that colonise the developing gut and to identify why some cells advance while others stay behind to populate a region. Directed cell migration is essential for normal development, including for the nervous system. In most of the migratory cell populations that have been analysed to date, all of the cells migrate as a collective from one location to another. However, there are also migratory cell populations that must populate the areas through which they migrate, and thus some cells get left behind while others advance. The planned data are likely to be relevant to other cell populations that also populate the areas through which they migrate, including neural crest-derived melanocytes and Schwann cell precursors.Read moreRead less