Victor Chang Cardiac Research Institute

Darlinghurst, Australia

Victor Chang Cardiac Research Institute

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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News Article | March 22, 2017

Laboratory Design (LD): How did you get into your field? David Keenan (DK): In an un-conventional way. I studied Zoology at University in the U.K., after which I joined a wine company that sent me to Edinburgh. After a couple of years, I realized I wanted to get back into science and found myself at the Medical Research Council’s Human Genetics Unit in Edinburgh working in a lab looking into the genetic disorders of muscle disease. The lab was successful and my boss was recruited to Sydney. He invited me to join him, so I left the U.K. to move to Australia, where I took on the role of setting up the lab and aquarium at the Victor Chang Cardiac Research Institute in Sydney. I thoroughly enjoyed this and it led to my next job, at the Garvan Institute. Over time I became responsible for planning and delivering larger and larger research buildings. My last project was the Victorian Comprehensive Cancer Center, a large $1 billion Public Private Partnership mixed health and research facility in Melbourne. I’ve now found my way to HDR. LD: What’s the most surprising thing you’ve learned in your career? DK: How close many door frames are to the height of a ULT-80 freezer, or how wide a double door is for a pallet movement/large piece of equipment. It is important to consider the items moving through any given door and, in particular, the full travel path for some large items to ensure usefulness and flexibility of the space. LD: What’s a common mistake made by those working on designing/constructing a laboratory? DK: The movement of materials and people through a lab is often not considered fully or in all situations. I’ve seen ramps in places where heavy loads are moved, or a single elevator at one end of a building that might often be on exclusive use. Then there are the issues of moving biological materials through non-lab environments to get from point A to B: Do you wear gloves or not, gowns or not; double-bag or not; are you traversing where people might eat/drink; and so on. These are all issues to be carefully considered in planning out how the spaces will be used. LD: What do you consider the highlight of your career? DK: It’s a tough pick but the Kinghorn Cancer Centre is a beautiful facility that is planned to be both functionally simple and, in my opinion, ‘elegant.’ The Victorian Comprehensive Cancer Centre is a close second for the sheer scale and challenge—everything about it was big! LD: If you could give just one piece of advice to others in your field, what would it be? LD: Can you describe a funny or exciting moment in your career? DK: A very exciting AND scary moment in my career had to be when we unveiled the Richard Long (U.K. Turner Prize-winning artist) artwork in the Kinghorn Cancer Centre. The artwork is a chalk mix on painted concrete that is eight stories high: spectacular in both scale and impact. There was a heart-stopping moment when a leak appeared during a freak torrential storm immediately after occupancy. Water tracked to just above the piece and began to run down the middle of the artwork … thankfully we repaired the leak immediately and the art wasn’t damaged but it was a scary time! LD: Is there anything else you’d like to share with the readers of Laboratory Design? DK: Don’t take yourself too seriously.

News Article | August 9, 2017

An extra dose of vitamin B3 might help prevent certain kinds of complex birth defects, according to a new study. The vitamin can help compensate for defects in the body’s ability to make a molecule, called nicotinamide adenine dinucleotide (NAD), which researchers have linked for the first time to healthy fetal development in humans. The find raises the possibility that boosting levels of B3 in pregnant women’s diets might help lower overall rates of birth defects. The story started with a search for genes that can cause heart defects. Sally Dunwoodie, a developmental geneticist at the Victor Chang Cardiac Research Institute in Sydney, Australia, and her colleagues study the genes that influence heart development, and for years doctors have connected them with families of children born with heart problems so that the team could try to pinpoint any responsible genes. In 2005, Dunwoodie’s team dealt with a particularly severe case: a baby who had major defects in the heart, backbone, and ribs—the rib problems were so severe that the child’s lungs couldn’t fully inflate. The team found that the family carried a mutation in a gene related to the production of NAD, a molecule crucial for energy storage and DNA synthesis in cells. Both parents carried a mutation in one of their copies of the gene, and the affected baby had inherited two defective copies. No one had reported any role for NAD in heart or bone development, Dunwoodie says. “We didn’t know what to do with it.” In 2012, however, the team found a related mutation in a family whose baby had a similar combination of defects. This time the mutant gene was involved in the next step in the reaction that makes NAD. “That was our Eureka moment,” Dunwoodie says. She and her colleagues eventually found that two more families who had children with similar birth defects had mutations in the same two genes. They describe the mutations from the four families today in The New England Journal of Medicine . To confirm the role of the mutations in organ and bone development, the researchers knocked out the two genes in mice to see whether similar birth defects appeared. At first all the pups were normal. But then the researchers realized that standard mouse chow is rich in niacin and that cells can use either niacin or nicotinamide—both known together as vitamin B3—to make NAD by an alternate pathway. So the scientists fed pregnant mutant mice a diet without it. Many pups died in utero, and those that survived had defects that closely resembled those seen in the four families’ affected children. Giving the mutant pregnant mice low doses of niacin led to pups with less severe defects, and a niacin-rich diet allowed the mutant mice to give birth to healthy litters. The work suggests that B3 supplements might help families with mutations in NAD-related genes, by preventing birth defects or perhaps even by treating already affected children. Of course, more human studies are needed before doctors could recommend B3 supplements for pregnant women, says Matthew Vander Heiden, who studies the role of NAD in cancer biology at the Massachusetts Institute of Technology in Cambridge. But the work opens a potentially exciting new area of research for developmental biologists: Trying to understand how cell metabolism affects development. Few people would have guessed that NAD deficiency causes birth defects, he says, “but it fits in with what we’ve been finding” about how NAD can influence cell growth. The researchers aren’t sure exactly how NAD levels affect development, because the molecule plays a key role in so many different cell functions. It might be that cells without enough NAD don’t have enough energy to keep up with the fast pace of cell growth and division that development requires. The molecule also helps cells respond to certain kinds of stress. But both Dunwoodie and Vander Heiden suspect the role NAD plays in DNA synthesis and repair might be especially important. They note that patients with Fanconi anemia, a disease in which DNA breaks easily, often have birth defects similar to those seen in the families in the study. Dunwoodie says she has counted at least 95 genes that are involved in NAD levels in the body. It’s possible that mutations in any of those could leave a developing fetus vulnerable to birth defects, even if neither parent has any obvious symptoms. Extra vitamin B3 in a mother’s diet might help compensate for any of the faulty genes, she says. Physicians already recommend that women consume specific amounts of folic acid, or vitamin B9, to prevent spinal cord defects, but the new work is not enough to offer a similar proposal for B3. Researchers need to learn more about how pregnancy influences NAD levels in general, and what a healthy level is, Vander Heiden says. It’s possible that the extra B3 in standard prenatal vitamins is already helpful. Too much niacin can cause dizziness, nausea, and diarrhea, but low doses don’t have any known side effects. “There’s little downside to adding a bit of niacin” to people’s diets, he says. If it could prevent even a few severe birth defects, “it’s a pretty exciting possibility.”

News Article | August 10, 2017

According to Australia's Victor Chang Cardiac Research Institute, one in four pregnant women will experience a miscarriage, and 7.9 million babies are born with a serious birth defect worldwide every year. A new study conducted at the institute, however, indicates that simply taking vitamin B3 could cause those numbers to drop drastically. In the study, led by Prof. Sally Dunwoodie, it was discovered that a molecule known as nicotinamide adenine dinucleotide (NAD) is essential to developing embryos. It's necessary for energy production, DNA repair and cell communication. Without it, miscarriages can occur, along with defects in the baby's heart, spine, kidneys and cleft palate. Vitamin B3 (aka niacin), which is found in meats and green vegetables, is required to make NAD. That said, even when they're taking general multivitamin supplements, it was found that a third of pregnant women have low levels of vitamin B3 in their first trimester – by the third trimester, 60 percent of women have low B3 levels. This would suggest that taking a specific vitamin B3 supplement in necessary. In tests performed on genetically-engineered lab mice, a large number of miscarriages and severe birth defects occurred when the mothers' B3 levels were kept low. Once those levels were boosted via dietary supplements, though, both the miscarriages and birth defects "were completely prevented." The scientists are now looking at developing a diagnostic test to measure NAD levels, which would identify pregnant women who are particularly in need of B3 supplements. "The ramifications are likely to be huge," says Dunwoodie. "This has the potential to significantly reduce the number of miscarriages and birth defects around the world, and I do not use those words lightly." A paper on the research was published this Thursday in the New England Journal of Medicine.

Agency: European Commission | 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.

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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