The Role Of The MYST Family Transcriptional Co-activator, Mof, In Embryonic Development
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
A major task in biology is to understand how the human genome directs the development of a single cell to form an entire individual. Clearly, a large part of this task is to understand how the expression of genes is regulated during embryonic development. Gene expression requires co-activator complexes. Co-activator complexes typically contain proteins which regulate the structure of chromatin (a complex of DNA and histones). However, the physiological function of most co-activators is entirely ....A major task in biology is to understand how the human genome directs the development of a single cell to form an entire individual. Clearly, a large part of this task is to understand how the expression of genes is regulated during embryonic development. Gene expression requires co-activator complexes. Co-activator complexes typically contain proteins which regulate the structure of chromatin (a complex of DNA and histones). However, the physiological function of most co-activators is entirely unclear. The aim of this project is to study the function of Mof during embryonic development. Mof is a co-activator that directly regulates chromatin structure by modifying histones. Mof is a member of the MYST family of co activators, which includes Moz and Qkf. We have recently shown that Moz and Qkf are essential for the haematopoietic stem cell population and the neural stem cell population, respectively. The purpose of this project is to produce a detailed analysis of the function of Mof in vivo and determine it's importance in regulating gene expression. All biological processes relay on accurate regulation of gene transcription and all diseases, whether they involve pathogens or cell intrinsic pathological changes, such as cancer, lead to changes in gene expression. Regulation of chromatin structure has been identified as a major mechanism of transcriptional regulation in health and disease. However, our understanding of the precise molecular mechanisms regulating chromatin structure in vivo are very limited. This work will fully investigate the role of an important co-activator in vivo including a mechanistic analysis. This will increase understanding of how gene expression is regulated and, ultimately, this knowledge will find wide application in the development of new treatment paradigms.Read moreRead less
The Role Of The MYST Family Lysine Acetyltransferase, Hbo1, In Development And In The Adult
Funder
National Health and Medical Research Council
Funding Amount
$403,368.00
Summary
This project will produce a detailed analysis of the function of Hbo1, a transcription factor, and determine its importance in regulating gene expression. All biological processes rely on accurate regulation of gene transcription and all diseases lead to changes in gene expression. This work will increase understanding of how gene expression is regulated and, ultimately, this knowledge will find wide application in the development of new treatment paradigms.
The Role Of The Mammalian Grainyhead-like Gene Family In Neural Tube Closure
Funder
National Health and Medical Research Council
Funding Amount
$569,541.00
Summary
Failure of the skin to close over the brain and spinal cord during human development results in the devastating congenital birth defects anencephaly and spina bifida, known collectively as the neural tube defects. These are the second most common congenital birth defects affecting 1:1000 pregnancies. Anencephaly is not compatible with life and affected babies die at birth. In contrast children with spina bifida survive, but suffer from limb paralysis, bowel and bladder dysfunction, learning diff ....Failure of the skin to close over the brain and spinal cord during human development results in the devastating congenital birth defects anencephaly and spina bifida, known collectively as the neural tube defects. These are the second most common congenital birth defects affecting 1:1000 pregnancies. Anencephaly is not compatible with life and affected babies die at birth. In contrast children with spina bifida survive, but suffer from limb paralysis, bowel and bladder dysfunction, learning difficulties and psycho-social disturbances. Our laboratories have identified a family of genes essential for the colsure of the neural tube in mammals. The aim of this proposal is to understand the mechanisms of action with a view to developing new therapeutics that mey be used preventatively in these conditions. We also hope that these studies may facilitate the development of a genetic test to screen couples at risk.Read moreRead less
Role Of Homeobox Gene Nkx2-5 In Heart Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$227,340.00
Summary
This project seeks to define the developmental principles underlying chamber formation in the developing heart and how this becomes abnormal in inherited heart defects. The gene we study, Nkx2-5, encodes a protein which binds to DNA and regulates the expression of the genetic program for formation of the ventricles, the pumping chambers of the heart. We believe that Nkx2-5 is an Oexecutive regulator? of this program, controlling the timing and spatial expression of other regulators that then con ....This project seeks to define the developmental principles underlying chamber formation in the developing heart and how this becomes abnormal in inherited heart defects. The gene we study, Nkx2-5, encodes a protein which binds to DNA and regulates the expression of the genetic program for formation of the ventricles, the pumping chambers of the heart. We believe that Nkx2-5 is an Oexecutive regulator? of this program, controlling the timing and spatial expression of other regulators that then control expression of a host of genes required for muscle differentiation and the development of form (morphogenesis). Mutations in one copy of the human Nkx2-5 gene have recently been discovered to be associated with atrial septal defect, or Ohole in the heartO, a sometimes serious inherited defect in heart structure. Mouse embryos with a mutation in both copies of the gene have a much more serious defect in ventricle formation that is incompatible with life. The studies are designed to extend our understanding of the genetic regulation of chamber formation in the heart. We will firstly make a mouse model of the human disease using gene targeting technology, which allows us to make precise alteration in single genes in this animal. Secondly, we will apply new technology to the heart that will let us visualise molecular and cellular events at higher resolution. This technology, which uses fluorescent tags on cells and a laser to measure cell identity, has been used to great affect in the field of immunology, but can be adapted to the heart. We will use it to isolate and characterise the precious early cells that give rise to the heart in the embryo. It is in these cells that the human and mouse mutations have their first effects. Our studies have relevance to understanding and screening for human inherited heart abnormalities, and for understanding the general principles of heart formation that may reveal valuable ways to intervene in heart disease.Read moreRead less
Understanding Human Dysmorphology Through Analysis Of ENU Mutant Mice
Funder
National Health and Medical Research Council
Funding Amount
$602,501.00
Summary
Birth defects are common and have an enormous impact on both the individual and their family. Birth defects are by definition the products of abnormal development of the embryo. Our research is aimed at identifying the normal mechanisms that usually prevail during development and the disturbances to those mechanisms that result in birth defects. These findings will lead to improved diagnostic, therapeutic and preventative options for families affected by birth defects
Rapid Identification And Characterisation Of Genes Involved In Skeletal Development
Funder
National Health and Medical Research Council
Funding Amount
$550,536.00
Summary
Birth defects are common and have an enormous impact on both the individual and their family. Birth defects are by definition the products of abnormal development of the embryo. Our research is aimed at identifying the normal mechanisms that usually prevail during development and the disturbances to those mechanisms that result in birth defects. These findings will lead to improved diagnostic, therapeutic and preventative options for families affected by birth defects
Preterm birth, a birth before the 37th week of pregnancy occurs for fewer than 8% of mothers but is associated with two-thirds of all fetal deaths and deaths of liveborn infants in the first month after birth. In the late 1990s those deaths are concentrated among very preterm births i.e. births before the 32nd week of pregnancy. Infants born very preterm are very likely to need neonatal intensive care, quite likely to have had major respiratory, infectious or other problems after birth, and to n ....Preterm birth, a birth before the 37th week of pregnancy occurs for fewer than 8% of mothers but is associated with two-thirds of all fetal deaths and deaths of liveborn infants in the first month after birth. In the late 1990s those deaths are concentrated among very preterm births i.e. births before the 32nd week of pregnancy. Infants born very preterm are very likely to need neonatal intensive care, quite likely to have had major respiratory, infectious or other problems after birth, and to need readmission to hospital in the first year after birth. Surviving infants are more likely to have major impairments, minor impairments, and school difficulties than infants born at term. There is a substantial impact on families, health services and society of very preterm birth.There has been no reduction in the proportion of births which are preterm, or very preterm in the last 20 years, though advances in treatment and care have markedly improved the survival of preterm and very preterm infants. This study will investigate the role of previous pregnancies which did not result in births (miscarriages and terminations), together with other procedures such as D and C (dilatation and curettage), in subsequent preterm birth. As these previous pregnancy losses are all fairly common experiences any associated risk is important and this particular factor has not been studied in this way before. There is preliminary evidence that they may be associated with preterm birth and the study will be able to measure the associations while taking into account all the other known risk factors. Other possible risk factors such as experiencing violence in pregnancy or social factors acting at a neighbourhood level will also be included. If it is found that previous pregnancy losses are independently associated with preterm birth it will be possible to develop and test preventive strategies.Read moreRead less
Noradrenaline Transporter Dysfunction In Neural Circulatory Disorders: Clinical, Molecular And Therapeutic Implications
Funder
National Health and Medical Research Council
Funding Amount
$510,870.00
Summary
We will investigate the clinical relevance of noradrenaline transporter (NET) dysfunction and its molecular and genetic regulation in (1) essential hypertension, (2) postural tachycardia syndrome where the heart rate increases abnormally when the patient assumes an upright position and (3) syncope where subjects experience recurrent blackouts. In a therapeutic approach, we will explore whether NET inhibition can reduce the number of episodes and alleviate the symptoms associated with syncope.
Molecular Mechanisms Regulating Spontaneous Onset Of Human Labour
Funder
National Health and Medical Research Council
Funding Amount
$481,156.00
Summary
The single most important complication contributing to poor pregnancy and neonatal outcome is premature birth. If we are to provide the best possible start to life, improve perinatal health and reduce the risk of developing adult disease . A better understanding of labour is requisite to improving health care delivery during pregnancy and outcomes for both mother and baby. This reserach project will investigate the how labour-associated events are reguluated by nuclear proteins.