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
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.
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.
Atrial Electrical Remodeling Due To Chronic Stretch: Defining The Substrate For Atrial Fibrillation
Funder
National Health and Medical Research Council
Funding Amount
$428,250.00
Summary
Background: Cardiac failure is a common heart disorder in which the pumping function of the heart is significantly weakened. Mitral regurgitation is a common condition where there is a leakage of blood from the left ventricle (lower heart chamber) back into the left atrium (upper heart chamber) during normal cardiac contraction. This puts a strain on the heart and may cause heart failure. Atrial septal defect is a common form of congenital heart disease which may not be diagnosed until adulthood ....Background: Cardiac failure is a common heart disorder in which the pumping function of the heart is significantly weakened. Mitral regurgitation is a common condition where there is a leakage of blood from the left ventricle (lower heart chamber) back into the left atrium (upper heart chamber) during normal cardiac contraction. This puts a strain on the heart and may cause heart failure. Atrial septal defect is a common form of congenital heart disease which may not be diagnosed until adulthood. There are several forms but the basic problem is leakage of blood from the left atrium into the right atrium .This also puts a strain on the heart and can cause heart failure. All 3 conditions are associated with a significantly increased risk of atrial fibrillation (AF). This abnormal fast irregular cardiac rhythm makes the pumping of the heart inefficient. People with AF may feel short of breath, tired, or develop palpitations. AF is an important cause of stroke and premature death and is the most common heart rhythm disturbance occurring in upto 10% of the over 70 age group. Even after repair of the leaky valve or atrial septal defect there is still a high risk of developing this rhythm. Purpose of the study: This study will try to understand why patients with these conditions are at risk of developing atrial fibrillation, and why this risk might persist after surgical correction when this is possible (mitral regurgitation and atrial septal defect). The study will utilise sophisticated new mapping techniques to gain original insights into the mechanism of this very common and as yet poorly understood heart rhythm disturbance. The study has the potential to determine the cause of atrial fibrillation in these patient groups and as such represent a quantum advance in our understanding of he mechanism of atrial fibrillation. It would be expected to form a foundation on which development of curative and preventative approaches may be based.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
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