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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
Role Of The T-box Transcription Factors, Tbx5 And Tbx20, In Cardiac Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$345,000.00
Summary
Structural defects in the heart are present in approximately 1 in 100 live births, and 1 in 10 still births in developed countries. Some 8% of deaths in the first year of life are caused by such abnormalities. While some defects can be repaired in childhood many go undetected and compound in later years leading to sudden death or compromised quality of life. Virtually all inherited heart defects for which the underlying genetic alteration is known are caused by mutations in genes controlling dev ....Structural defects in the heart are present in approximately 1 in 100 live births, and 1 in 10 still births in developed countries. Some 8% of deaths in the first year of life are caused by such abnormalities. While some defects can be repaired in childhood many go undetected and compound in later years leading to sudden death or compromised quality of life. Virtually all inherited heart defects for which the underlying genetic alteration is known are caused by mutations in genes controlling development of the heart in the embryo. Examples are Tbx5, a member of the T-box family of transcription factor genes mutated in Holt Oram syndrome, and Nkx2-5, a homeodomain transcription factor gene mutated in families with hole in the heart and cardiac electrical defects. We propose to investigate the involvement of a new member of the T-box gene family, Tbx20, in cardiac development and disease, and to compare and contrast its function with that of Tbx5. The Tbx5 and Tbx20 proteins interact directly with Nkx2-5 to stimulate transcription of cardiac genes, making Tbx20 a good candidate for involvement in inherited disease. We will use gene targeting technology to delete the Tbx20 gene in mice, and will analyse heart anatomy, gene expression and function to determine the effect of its loss. We will also investigate how Tbx20 interacts with other cardiac regulatory pathways, by crossing Tbx20 mutant mice with mice deficient for Nkx2-5 and Tbx5, strains that show heart abnormalities similar to those found in human patients. Microarray technology, which examines gene expression on a whole genome scale, will also be used to identify genes that are regulated by these transcription factors. Finally, we will search for mutations in the Tbx20 gene in human patients that have inherited heart abnormalities. In doing so we may improve our understanding of disease causation and predisposition thereby identifying patients at risk and providing improved genetic counselling and diagnosis.Read moreRead less
Coronary artery disease is the largest single cause of death in Australia, and commonly manifests as heart attack and angina. Congenital heart disease is the most common birth defect. We have identified a gene, Crim1, that is important for heart and coronary artery development. Investigating how this gene functions will lead to a greater understanding of congenital heart disease and may lay the foundation for therapeutics to regenerate damaged hear tissue.
Genetic And Molecular Dissection Of Laterality In The Developing Heart
Funder
National Health and Medical Research Council
Funding Amount
$379,370.00
Summary
Vertebrate animals display an external bilateral symmetry. However, most internal organs are located asymmetrically and show profound left-right structural asymmetries during development. For each species, these laterality characteristics are constant. Inherited laterality disorders occur in humans and, although rare, are associated with high mortality rates due to discordant cardiovascular development. Moreover, subtle anomalies of laterality may underlie a host of congenital heart abnormalitie ....Vertebrate animals display an external bilateral symmetry. However, most internal organs are located asymmetrically and show profound left-right structural asymmetries during development. For each species, these laterality characteristics are constant. Inherited laterality disorders occur in humans and, although rare, are associated with high mortality rates due to discordant cardiovascular development. Moreover, subtle anomalies of laterality may underlie a host of congenital heart abnormalities. In early embryogenesis, the newly-formed heart tube loops to the right, an event which establishes the correct alignment of the future cardiac chambers. The direction of heart looping is determined by genetic pathways that establish laterality in the early embryo. A component of this pathway is a TGFbeta-family signalling molecule, nodal, which is activated on the left side of the forming heart and other organs. Nodal then activates the transcription factor gene Pitx2. The aim of this project is to examine the consequences of genetic inactivation of the mouse nodal and Pitx2 genes in the heart, and to discover cardiac genes downstream of these genes. We will specifically test the hypothesis that laterality contributes to heart chamber formation in addition to setting the direction of looping. Ablation of these genes in the whole embryo leads to complex defects that preclude analysis of their functions in the heart. To achieve heart-specific deletion, we will use a conditional gene ablation technology that exploits the bacteriophage recombinase, Cre. Genes downstream of Pitx2 and Nodal will be discovered using microarray technology, which allows us to screen exhaustively for changes in gene expression between different tissues. This project will help us solve the complex genetic basis of congenital cardiac abnormalities in humans, and will contribute to our understanding of how heart chambers form, potentially useful in stem cell-based therapies for the failing heart.Read moreRead less
Does Remote Ischemic Preconditioning Induce Protective Mitochondrial Function In Congenital Heart Defect Repair Surgery?
Funder
National Health and Medical Research Council
Funding Amount
$142,759.00
Summary
The body's own protective mechanism against injury due to reduced blood flow (ischemic preconditioning) has been studied for over 2 decades, yet the clinical benefits have not been realised until recently . We have previously shown that this innate protection can be induced without drugs in children having heart surgery. We will extend these findings to determine the mechanism of protection, develop a method to monitor this in blood cells and see if this is related to post-operative outcomes.
Role Of Homeobox Gene Nkx2-5 In Heart Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$143,250.00
Summary
Congenital abnormalities of the heart occur in ~1 in 100 live births and 1 in 10 still births in Western populations. The genetic pathways underlying cardiac development are now being dissected with increasing vigour in an effort to understand both the morphological progressions and genetic basis of heart defects. Mutations in a cardiac gene called Nkx2-5, which encodes a transcriptional regulatory protein, can cause heart defects in human families and isolated individuals, most predominantly at ....Congenital abnormalities of the heart occur in ~1 in 100 live births and 1 in 10 still births in Western populations. The genetic pathways underlying cardiac development are now being dissected with increasing vigour in an effort to understand both the morphological progressions and genetic basis of heart defects. Mutations in a cardiac gene called Nkx2-5, which encodes a transcriptional regulatory protein, can cause heart defects in human families and isolated individuals, most predominantly atrial septal defect (hole in the heart) associated with an abnormality in electrical activity of the heart. Nkx2-5 is expressed in the precursor cells of the muscle and other lineages that make up the heart in the embryo, then in the muscle layer of the heart throughout foetal and adult life. Mouse hearts that lack the Nkx2-5 gene altogether arrest at an early stage of heart development showing a complete block to ventricular chamber formation. Mice lacking only one copy of the Nkx2-5 gene have ASD and electrical defects, similar to the human disease. Building on these findings we have developed a suite of new genetic reagents with which to gain a deeper understanding of the role of Nkx-5 in development and disease. These include a mouse strain from which Nkx2-5-positive muscle cells can be purified away from other cell types in the heart, and another mouse strain that represents a good model for common congenital heart defects. We will further investigate the role of Nkx2-5 in allocation of cell types in the heart, chamber formation and birth defects using these reagents.Read moreRead less
Understanding The Role That Cellular Hypoxia Plays In Normal Heart Development
Funder
National Health and Medical Research Council
Funding Amount
$522,773.00
Summary
Congenital heart defects (CHD) are the most common type of birth defects, being present in 6 out of every 1000 live births, and 10% of stillbirths. In addition to the danger of death during childhood, such heart defects also increase the risk of heart disease during adulthood. Our research project involves looking for the genetic causes of CHD. We are looking at two genes , called HIF1a and CITED2, for which we already have evidence that they are very important in allowing the heart to form norm ....Congenital heart defects (CHD) are the most common type of birth defects, being present in 6 out of every 1000 live births, and 10% of stillbirths. In addition to the danger of death during childhood, such heart defects also increase the risk of heart disease during adulthood. Our research project involves looking for the genetic causes of CHD. We are looking at two genes , called HIF1a and CITED2, for which we already have evidence that they are very important in allowing the heart to form normally within the embryo. Because the heart is the first organ to form in the embryo (during the first trimester), we cannot use humans to study this process. Instead we have two lines of mice which specifically lack either the HIF1a or CITED2 genes throughout the embryo. Both of these mouse lines have severe heart defects similar to some types of CHD seen in humans. However, removal of either of these genes also causes severe defects in other tissues, complicating our study. To overcome this problem, we will use a slightly different technique to remove either gene specifically in the entire developing heart of the embryo, while leaving the normal gene in the rest of the embryo. Thus we will be able for the first time to study the effects of these genes on the heart alone. We suspect that the defects in the hearts of such embryos will be of a particular sub-type of CHD. If this is true, in the future we hope to be able show that mutation of either of these genes will cause a specific type of human CHD. This will enable genetic screening of families with a history of CHD, assist in genetic counselling, and promote the development of therapies.Read moreRead less
Human Factors And Patient Safety During Paediatric Heart Surgery: An Evidence-based Approach To Improve Patient Outcomes
Funder
National Health and Medical Research Council
Summary
The research project aims to improve outcomes of children undergoing repair of heart birth defects. The novel study is devised to engage health care providers in the re-design of surgical interventions to improve child outcomes. The collaborative approach of engaging health care providers and carers in the design of improvement interventions can help overcome the implementation gap and ensure rapid improvement and enhanced patient safety of children undergoing heart surgery repair.
The Australia And New Zealand Fontan Registry: A Growing Population Of Young Adults With Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$129,103.00
Summary
The Fontan procedure is an operation performed for all children with heart defects who cannot be repaired with 2 pumping chambers like a normal heart. It is expected that after 2 or 3 decades, these patients will either die or need a heart transplantation. We want to establish a registry to evaluate the number and status of this increasing patient population. This study may foresee and even prevent a sudden burden on the health system caused by their needs.
THE ROLES OF CYTOSKELETAL PROTEINS IN SKELETAL MUSCLE FUNCTION AND DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$466,650.00
Summary
Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early chilhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In nemaline myopathy pat ....Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early chilhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In nemaline myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of the sarcomere. Therefore, the genes for other thin filament, thick filament and Z-line proteins are excellent candidates for these disorders. Research from our lab has identified a novel region of the sarcomere and the genes encoding the proteins present in this region provide additional candidates for the congenital myopathies. We will further characterise the proteins in this novel structure to determine its function and the role that it plays in muscle disease pathologies. In order to study the relationship between disease pathology and muscle weakness in nemaline myopathy, we generated a mouse model by expressing a mutant protein, a-tropomyosin slow, found in human patients in mice. All features of the disease found in humans are present in the mice. A key feature of this disease in mice is the ability for muscle cells to grow in diameter or hypertrophy to offset the muscle weakness. We will use these mice to trial therapies including hypertropy-inducing agents, to prevent and reverse muscle weakness. In addition, we will generate an additional mouse model for this disease with a mutation in a gene encoding another filamentous protein. A comparison of the two models using microarray analysis will help us identify additional genes that are being affected in this disease and to generate a molecular expression profile that will aid in the diagnosis of this disease.Read moreRead less