Darlinghurst, Australia
Darlinghurst, Australia

The Victor Chang Cardiac Research Institute is an independent, not-for-profit research facility, based in Darlinghurst, New South Wales, Australia. The Institute was founded in memory of pioneering cardiac surgeon Dr. Victor Chang and his passionate belief in the power of discovery.Established on 15 February 1994, approximately three years after Dr. Chang's death, and opened by then Prime Minister Paul Keating, the Institute has become a world-class research and research training facility. Wikipedia.


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Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.2-4 | Award Amount: 3.94M | Year: 2009

Cardiovascular malformation (CVM) is the commonest cause of childhood death in developed countries. In the EU there are 51,000 new cases each year and two million affected individuals. Yet, despite intensive research, the cause of 80% of CVM remains elusive. The mission of CHeartED is to identify genetic and environmental pathways that can be modified with the goal of reducing preventable CVM incidence. Epidemiological studies have shown that the stress of maternal hypo or hyperglycaemia increases the incidence of CVM. We plan a genetic association study in individuals with and without CVM born to diabetic mothers, to test whether genetic variants are associated with CVM. A similar study, without prior risk hypothesis, addresses tetralogy of Fallot, a CVM, which requires surgery in early life. These studies will reveal common genetic variants associated with CVM and thus add to existing knowledge on the aetiology of CVM. Moreover, the identification of genetic factors that differ in the context of maternal diabetes will disclose any associations in genetic pathways influenced by environmental factors. RNA expression studies in the mouse to identify new genes and pathways involved in outflow tract malformations and maternal diabetes associated with CVM, will complement the human studies. Finally, we will develop a 3D atlas of gene expression patterns and cardiac morphology at key developmental stages that will serve as a morphological framework. Central to our proposal is the development of a bioinformatics tool complemented by an open-access Wiki-based database. The bioinformatics tool will combine the sequence data and expression data generated by the human and mouse studies with morphology and literature to prioritize genes and generate hypotheses. The Wiki, which will contain existing and new genetic and environmental knowledge on heart development, will be an aid for many groups working on cardiovascular development and a novel means of disseminating our findings


Grant
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2011.2.2.1-2 | Award Amount: 17.04M | Year: 2012

NEURINOX aims at elucidating the role of NADPH oxidases (NOX) in neuroinflammation and its progression to neurodegenerative diseases (ND), as well as evaluating the potential of novel ND therapeutics approaches targeting NOX activity. NOX generate reactive oxygen species (ROS) and have emerged as regulators of neuroinflammation. Their role is complex: ROS generated by NOX lead to tissue damage in microglia-mediated neuroinflammation, as seen in amyotrophic lateral sclerosis (ALS), while absence of ROS generation enhances the severity of autoimmune-mediated neuroinflammation, as seen for e.g. in multiple sclerosis (MS). The objective of the 5 years NEURINOX project is to understand how NOX controls neuroinflammation, identify novel molecular pathways and oxidative biomarkers involved in NOX-dependent neuroinflammation, and develop specific therapies based on NOX modulation. The scientific approach will be to: (i) identify NOX-dependent molecular mechanisms using dedicated ND animal models (ii) develop therapeutic small molecules either inhibiting or activating NOX and test their effects in animal models (iii) test the validity of identified molecular pathways in clinical studies in ALS and MS patients. NEURINOX will contribute to better understand brain dysfunction, and more particularly the link between neuroinflammation and ND and to identify new therapeutic targets for ND. A successful demonstration of the benefits of NOX modulating drugs in ALS and MS animal models, and in ALS early clinical trials will validate a novel high potential therapeutics target for ALS and also many types of ND. NEURINOX has hence a strong potential for more efficient ND healthcare for patients and thus for reducing ND healthcare costs. This multi-disciplinary consortium includes leading scientists in NOX research, ROS biology, drug development SMEs, experts in the neuroinflammatory aspects of ND, genomics and proteomics, and clinicians able to translate the basic science to the patient.


Martinac B.,Victor Chang Cardiac Research Institute | Martinac B.,University of New South Wales
Biochimica et Biophysica Acta - Biomembranes | Year: 2014

As biological force-sensing systems mechanosensitive (MS) ion channels present the best example of coupling molecular dynamics of membrane proteins to the mechanics of the surrounding cell membrane. In animal cells MS channels have over the past two decades been very much in focus of mechanotransduction research. In recent years this helped to raise awareness of basic and medical researchers about the role that abnormal MS channels may play in the pathophysiology of diseases, such as cardiac hypertrophy, atrial fibrillation, muscular dystrophy or polycystic kidney disease. To date a large number of MS channels from organisms of diverse phylogenetic origins have been identified at the molecular level; however, the structure of only few of them has been determined. Although their function has extensively been studied in a great variety of cells and tissues by different experimental approaches it is, with exception of bacterial MS channels, very little known about how these channels sense mechanical force and which cellular components may contribute to their function. By focusing on MS channels found in animal cells this article discusses the ways in which the connections between cytoskeleton and ion channels may contribute to mechanosensory transduction in these cells. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé. © 2013 Elsevier B.V.


Del Monte G.,Victor Chang Cardiac Research Institute | Harvey R.P.,Victor Chang Cardiac Research Institute | Harvey R.P.,University of New South Wales
Cell | Year: 2012

Despite the profound impact of coronary artery disease on human health, the origins of the coronary blood vessels are poorly understood. Wu et al. use imaging and genetic techniques to show that the endocardium contributes to the coronary vessels and that the coronary arteries and veins have multilineage origins. © 2012 Elsevier Inc.


Patent
Yeda Research, Development Co. and Victor Chang Cardiac Research Institute | Date: 2016-05-05

A method of potentiating cardiac regeneration with neuregulin treatment in a subject in need thereof. The method comprising administering to the subject a therapeutic effective amount of an agent which upregulates activity or expression of ErbB-2, thereby potentiating cardiac regeneration with neuregulin treatment.


Kikuchi K.,Victor Chang Cardiac Research Institute | Poss K.D.,Howard Hughes Medical Institute
Annual Review of Cell and Developmental Biology | Year: 2012

The heart holds the monumental yet monotonous task of maintaining circulation. Although cardiac function is critical to other organs and to life itself, mammals are not equipped with significant natural capacity to replace heart muscle that has been lost by injury. This deficiency plays a role in leaving millions worldwide vulnerable to heart failure each year. By contrast, certain other vertebrate species such as zebrafish are strikingly good at heart regeneration. A cellular and molecular understanding of endogenous regenerative mechanisms and advances in methodology to transplant cells together project a future in which cardiac muscle regeneration can be therapeutically stimulated in injured human hearts. This review focuses on what has been discovered recently about cardiac regenerative capacity and how natural mechanisms of heart regeneration in model systems are stimulated and maintained. Copyright © 2012 by Annual Reviews. All rights reserved.


Cropley J.E.,Victor Chang Cardiac Research Institute
Proceedings. Biological sciences / The Royal Society | Year: 2012

Natural selection acts on variation that is typically assumed to be genetic in origin. But epigenetic mechanisms, which are interposed between the genome and its environment, can create diversity independently of genetic variation. Epigenetic states can respond to environmental cues, and can be heritable, thus providing a means by which environmentally responsive phenotypes might be selectable independent of genotype. Here, we have tested the possibility that environment and selection can act together to increase the penetrance of an epigenetically determined phenotype. We used isogenic A(vy) mice, in which the epigenetic state of the A(vy) allele is sensitive to dietary methyl donors. By combining methyl donor supplementation with selection for a silent A(vy) allele, we progressively increased the prevalence of the associated phenotype in the population over five generations. After withdrawal of the dietary supplement, the shift persisted for one generation but was lost in subsequent generations. Our data provide the first demonstration that selection for a purely epigenetic trait can result in cumulative germline effects in mammals. These results present an alternative to the paradigm that natural selection acts only on genetic variation, and suggest that epigenetic changes could underlie rapid adaptation of species in response to natural environmental fluctuations.


Vandenberg J.I.,Victor Chang Cardiac Research Institute
Physiological reviews | Year: 2012

The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11.1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.1 channels play in the heart that has been best characterized, for two main reasons. First, it is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death. Second, blockade of Kv11.1, by a wide range of prescription medications, causes drug-induced QT prolongation with an increase in risk of sudden cardiac arrest. In the first part of this review, the properties of Kv11.1 channels, including biogenesis, trafficking, gating, and pharmacology are discussed, while the second part focuses on the pathophysiology of Kv11.1 channels.


Hynson R.M.G.,Victor Chang Cardiac Research Institute
Nature Structural and Molecular Biology | Year: 2016

Large protein complexes assemble spontaneously, yet their subunits do not prematurely form unwanted aggregates. This paradox is epitomized in the bacterial flagellar motor, a sophisticated rotary motor and sensory switch consisting of hundreds of subunits. Here we demonstrate that Escherichia coli FliG, one of the earliest-assembling flagellar motor proteins, forms ordered ring structures via domain-swap polymerization, which in other proteins has been associated with uncontrolled and deleterious protein aggregation. Solution structural data, in combination with in vivo biochemical cross-linking experiments and evolutionary covariance analysis, revealed that FliG exists predominantly as a monomer in solution but only as domain-swapped polymers in assembled flagellar motors. We propose a general structural and thermodynamic model for self-assembly, in which a structural template controls assembly and shapes polymer formation into rings. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Fatkin D.,Victor Chang Cardiac Research Institute
Cold Spring Harbor perspectives in medicine | Year: 2014

Cardiomyopathies are a heterogeneous group of heart muscle diseases associated with heart failure, arrhythmias, and death. Genetic variation has a critical role in the pathogenesis of cardiomyopathies, and numerous single-gene mutations have been associated with distinctive cardiomyopathy phenotypes. Contemporaneously with these discoveries, there has been enormous growth of genome-wide sequencing studies in large populations, data that show extensive genomic variation within every individual. The considerable allelic diversity in cardiomyopathy genes and in genes predicted to impact clinical expression of disease mutations indicates the need for a more nuanced interpretation of single-gene mutation in cardiomyopathies. These findings highlight the need to find new ways to interpret the functional significance of suites of genetic variants, as well as the need for new disease models that take global genetic variant burdens, epigenetic factors, and cardiac environmental factors into account.

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