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
Genetic Control Of Body Patterning: Intersection Of Transcriptional And Signalling Activity In Head Formation
Funder
National Health and Medical Research Council
Funding Amount
$579,932.00
Summary
A most critical step in embryonic development is the assembly of the different tissue components into a three-dimensional structure in order to build a major body part of the foetus. The objective of our research is to understand how the mechanisms that control genetic activity and cell-to-cell signalling may cooperate in the formation of the head and face of the embryo. The outcome will focus future clinical investigations to the most relevant genetic determinants of craniofacial defects.
Molecular Genetics Of Sex Determination And Gonad Development
Funder
National Health and Medical Research Council
Funding Amount
$539,000.00
Summary
Disorders of sexual development are among the most common forms of birth defects in humans (1 in 4,000 births). Many other childhood conditions with this incidence warrant prenatal diagnosis or neonatal screening. These disorders often result in infertility, genital abnormalities and gender mis-assignment. Uncertainty about a child s gender at birth can be very traumatic physically and psychologically for the individual and family concerned. There are profound consequences in later life for the ....Disorders of sexual development are among the most common forms of birth defects in humans (1 in 4,000 births). Many other childhood conditions with this incidence warrant prenatal diagnosis or neonatal screening. These disorders often result in infertility, genital abnormalities and gender mis-assignment. Uncertainty about a child s gender at birth can be very traumatic physically and psychologically for the individual and family concerned. There are profound consequences in later life for the affected individual. The cause of these problems is most often the failure of the delicate network of gene regulation that is responsible for proper development of testes or ovaries in the embryo. This research project will identify genes important for sex determination and development of the gonads, find out how these genes function and interact, and discover how they contribute to cases of aberrant sexual development in humans.Read moreRead less
Characterization Of The Phosphoinositide 5-phosphatase SKIP.
Funder
National Health and Medical Research Council
Funding Amount
$505,523.00
Summary
Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our grant proposes to investigate the function of another enzym ....Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our grant proposes to investigate the function of another enzyme called SKIP which acts within the cell to oppose the functions of the PI3-kinase. Several lines of evidence indicate SKIP may be important in both development and cancer. SKIP has been identified as a putative candidate gene for a developmental disorder known as Miller Dieker syndrome. This disease is associated with facial and significant brain abnormalities. In addition the SKIP gene is located on a chromosome that is frequently deleted in breast and colon cancer. SKIP is an enzyme that functions to remove phosphate molecules from PI3-kinase signaling molecules. SKIP has been shown to prevent glucose uptake into the cell by breaking down PI3-kinase signals. We have recently demonstrated SKIP phosphatase activity can be inhibited by binding to another protein called suppressor of death domains (SODD). We plan to investigate the effects this complex has on SKIP enzyme activity, and how this complex plays a role in regulating PI3-kinase signals that promote glucose uptake. Secondly, we plan to investigate the function of SKIP in an intact animal by making mice which lack SKIP(knock out mice). Given SKIP is implicated in a developmental syndrome and insulin signaling, we can delineate the functional significance of SKIP and the molecular pathways regulated by this enzyme.Read moreRead less
Copy Number Analysis Of Patients With Gonadal Abnormalities Using High Density Microarrays And MLPA
Funder
National Health and Medical Research Council
Funding Amount
$311,187.00
Summary
Congenital conditions in which development of the gonads or anatomical sex is abnormal are surprisingly common. The underlying cause of these problems is most often the failure of genes responsible for proper development of testes or ovaries. Only a small proportion of patients can be explained by mutations in known gonad determining genes. We will analyse DNA from these patients on very high density microarrays to identify new genes that cause abnormalities in testis and ovary development.
Cellular And Molecular Regulation Of Fetal Ovarian Development
Funder
National Health and Medical Research Council
Funding Amount
$547,315.00
Summary
Normal development of the ovaries is critical for women's health and reproduction. Recent studies have shown that even the very earliest steps in ovarian development, occurring during fetal growth, can play a major part in predisposing to some of the most common and debilitating reproductive and endocrine disorders affecting Australian women. In this project we will take a systematic and comprehensive approach to exploring the mysteries of fetal ovary development, discovering what genes need to ....Normal development of the ovaries is critical for women's health and reproduction. Recent studies have shown that even the very earliest steps in ovarian development, occurring during fetal growth, can play a major part in predisposing to some of the most common and debilitating reproductive and endocrine disorders affecting Australian women. In this project we will take a systematic and comprehensive approach to exploring the mysteries of fetal ovary development, discovering what genes need to be activated and what cellular processes are required for normal ovary development and hence may play a part in ovarian diseases that manifest in later life. This work will offer new avenues for the prevention, diagnosis and treatment of ovarian disease and female infertility.Read moreRead less
INVESTIGATING THE VALIDITY OF PRENATAL INSULTS AS RISK FACTORS FOR SCHIZOPHRENIA.
Funder
National Health and Medical Research Council
Funding Amount
$201,100.00
Summary
Schizophrenia is one of the most devastating of human mental disorders affecting about 1% of the population. The cause of this disorder is not known but it seems certain that it will involve genetic and environmental factors. An adverse environmental factor could be a reduced supply of oxygen and nutrients to a baby during pregnancy. In guinea pigs we aim to investigate whether disruption to the normal supply of oxygen and nutrients to the fetus disrupts the normal fine structure and chemical ma ....Schizophrenia is one of the most devastating of human mental disorders affecting about 1% of the population. The cause of this disorder is not known but it seems certain that it will involve genetic and environmental factors. An adverse environmental factor could be a reduced supply of oxygen and nutrients to a baby during pregnancy. In guinea pigs we aim to investigate whether disruption to the normal supply of oxygen and nutrients to the fetus disrupts the normal fine structure and chemical make up of the brain and gives rise to long-lasting structural and neurochemical changes in adolescent animals, which resemble changes found in the brains of patients with schizophrenia. We will also assess whether behavioural responses of compromised animals are altered in tests that parallel disturbances seen in patients with schizophrenia. Such abnormal brain development could create an underlying vulnerability in the brain, predisposing individuals with risk factors such as genetic inheritance to develop the symptoms of schizophrenia in later life perhaps only after the complete formation of nerve pathways involved in higher brain functioning. If guinea pigs that have been subjected to low oxygen levels during pregnancy show sustained changes in the structure and neurochemistry in regions of the brain that are altered in patients with schizophrenia it would suggest that these long lasting disturbances could result from problems during pregnancy. Thus, this would support the idea that abnormal brain development during pregnancy is one of the underlying causes of schizophrenia.Read moreRead less
Long Term Outcome From Early Childhood Brain Injury: 10 Year Follow Up
Funder
National Health and Medical Research Council
Funding Amount
$338,900.00
Summary
The primary aim of this project is to further improve our understanding of the long-term consequences of childhood traumatic brain injury (TBI). Over the past decade our research team has ascertained a sample of children sustaining TBI, and systematically followed their progress over a 5-year period. The project has an international reputation, and is unique in terms of length of follow-up, prospective design and representative, well-maintained sample. Our findings challenge the traditionally he ....The primary aim of this project is to further improve our understanding of the long-term consequences of childhood traumatic brain injury (TBI). Over the past decade our research team has ascertained a sample of children sustaining TBI, and systematically followed their progress over a 5-year period. The project has an international reputation, and is unique in terms of length of follow-up, prospective design and representative, well-maintained sample. Our findings challenge the traditionally held view that children are resilient and recover fully from early brain insult. Rather, we have shown that, up to 5 years post-TBI, many children experience impairments in physical, cognitive and behavioural function. These impairments result in educational, vocational, social and emotional problems, limiting the child's capacity to meet developmental expectations and achieve adequate quality of life. The implication is that these problems will lead to life-long disability, resulting in high levels of individual, family and community burden. However, with follow-up data limited to 5 years, there remains a possibility that ongoing developmental processes may support an extended recovery period in childhood TBI, in comparison to the 2-year period cited in adult models. The review of this sample, 10 years post-injury, provides an unprecedented opportunity to address this possibility and to document recovery-outcome as children move into adolescence and adulthood. Not all children experience problems post-injury. However, predicting individual outcome remains a significant challenge, with particular clinical relevance to treatment and follow-up. Thus, the second aim of the proposed study is to examine factors that contribute to recovery and outcome.Read moreRead less
We have identified a novel gene, Inpp5e, that when mutated causes a disease similar to Joubert syndrome and MORMS disease which leads to abnormal movements, developmental delays, mental retardation, abnormal breathing and eye movement. We have identified a candidate gene for these diseases and have shown that deletion of this gene in mice results in similar pathology. We aim to determine the mechanism by which Inpp5e regulates human development and disease.
Does Maladaptive Remodelling Of The Heart And Vasculature In Response To Preterm Birth Lead To Long-term Cardiovascular Risk?
Funder
National Health and Medical Research Council
Funding Amount
$535,086.00
Summary
Being born prematurely is linked to the development of high blood pressure (a major risk factor for cardiovascular disease) later in life. In this project we will examine whether injury to the cells lining the cardiovascular system and/or structural changes in the wall of the arteries and the heart, as a result of being born early, lead to an elevation in blood pressure and heart dysfunction in adulthood.