Hudson Institute of Medical Research
Hudson Institute of Medical Research
Giles E.M.,Monash Medical Center |
Giles E.M.,Hudson Institute of Medical Research |
Stagg A.J.,Monash Medical Center |
Stagg A.J.,Queen Mary, University of London
Inflammatory Bowel Diseases | Year: 2017
The human gut is in constant complex interaction with the external environment. Although much is understood about the composition and function of the microbiota, much remains to be learnt about the mechanisms by which these organisms interact with the immune system in health and disease. Type 1 interferon (T1IFN), a ubiquitous and pleiotropic family of cytokines, is a critical mediator of the response to viral, bacterial, and other antigens sampled in the intestine. Although inflammation is enhanced in mouse model of colitis when T1IFN signaling is lost, the action of T1IFN is context specific and can be pro- or anti-inflammatory. In humans, T1IFN has been used to treat inflammatory diseases, including multiple sclerosis and inflammatory bowel disease but intestinal inflammation can also develop after the administration of T1IFN. Recent findings indicate that "tonic" or "endogenous" T1IFN, induced by signals from the commensal microbiota, modulates the local signaling environment to prime the intestinal mucosal immune system to determine later responses to pathogens and commensal organisms. This review will summarize the complex immunological effects of T1IFN and recent the role of T1IFN as a mediator between the microbiota and the mucosal immune system, highlighting human data wherever possible. It will discuss what we can learn from clinical experiences with T1IFN and how the T1IFN pathway may be manipulated in the future to maintain mucosal homeostasis. Copyright © 2017 Crohn's & Colitis Foundation of America, Inc.
Lim R.,Hudson Institute of Medical Research |
Lim R.,Monash University
Stem Cells Translational Medicine | Year: 2017
The clinical application of the fetal membranes dates back to nearly a century. Their use has ranged from superficial skin dressings to surgical wound closure. The applications of the fetal membranes are constantly evolving, and key to this is the uncovering of multiple populations of stem and stem-like cells, each with unique properties that can be exploited for regenerative medicine. In addition to pro-angiogenic and immunomodulatory properties of the stem and stem-like cells arising from the fetal membranes, the dehydrated and/or decellularized forms of the fetal membranes have been used to support the growth and function of other cells and tissues, including adipose-derived mesenchymal stem cells. This concise review explores the biological origin of the fetal membranes, a history of their use in medicine, and recent developments in the use of fetal membranes and their derived stem and stem-like cells in regenerative medicine. Stem Cells Translational Medicine 2017;6:1767–1776. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press
Yang J.,Hudson Institute of Medical Research |
Yang J.,Monash University |
Young M.J.,Hudson Institute of Medical Research |
Young M.J.,Monash University
Current Opinion in Pharmacology | Year: 2016
Mineralocorticoid receptor antagonists (MRAs) are best known as potassium-sparing diuretics due to their blockade of aldosterone action in renal epithelial tissues. They are also beneficial for the treatment of heart failure, primarily due to effects in non-epithelial tissues. Currently there are only two steroidal MRAs that have been approved for use; spironolactone (and its active metabolite canrenone) and eplerenone. However, the search is on for novel generations of MRAs with increased potency and tissue selectivity. A number of novel non-steroidal compounds are in preclinical and early development, with one agent moving to phase III trials. The development of these agents and the mechanisms for their pharmacologic superiority compared to earlier generations of MRAs will be discussed in this review. © 2016 Elsevier Ltd. All rights reserved.
News Article | December 5, 2016
Researchers from Massachusetts General Hospital (MGH) and the University of California, Riverside, have shown for the first time that RNA interference (RNAi) - an antiviral mechanism known to be used by plants and lower organisms - is active in the response of human cells to some important viruses. In their report receiving advance online publication in Nature Microbiology, the investigators document both the production of RNAi molecules in human cells infected with the influenza A virus and the suppression of RNAi defense by a viral protein known to block the process in a common animal model. "Viruses are the most abundant infectious agents and are a constant threat to human health," says Kate Jeffrey, PhD, of the Gastrointestinal Unit in the MGH Department of Medicine, co-corresponding author of the paper. "Vaccines are somewhat effective but can have limited use when viruses like influenza rapidly mutate from year to year. Identifying therapeutic targets within patients that could help them fight off an infection is a critical strategy for combating the spread of common, often-dangerous viruses." First described in the 1990s - a discovery that led to the 2006 Nobel Prize - RNAi is a process by which organisms suppress the expression of target genes through the action of small RNA segments that bind to corresponding gene sequences. Not only is RNAi used to regulate gene expression within an organism, it also can combat viral infection by silencing the activity of viral genes required for the pathogen's replication. Whether or not RNAi contributes to antiviral defense in mammals has been uncertain. The only previous demonstration - by researchers led by Shou-Wei Ding, PhD, a professor of Plant Pathology and Microbiology at UC Riverside and co-corresponding author of the current study - was done in embryonic stem cells and in newborn mice. Ding has been studying antiviral RNAi for more than two decades and also was the first to describe the action of the influenza virus protein NS1 in blocking RNAi in fruit flies. His team collaborated with investigators from Jeffrey's laboratory to investigate whether or not an RNAi response is induced in human and mouse cells infected with the influenza virus, one of many important viruses using RNA as its genetic material. Their experiments verified that influenza-A-infected mature human cells do generate the small RNA segments used in RNAi but that virally-produced NS1 blocks the processing of those molecules into the complexes that bind to and silence their target genes. If cells were infected with an influenza A mutant lacking NS1, they proceeded to produce large number of the molecular complexes required for RNAi, which include a protein called Argonaute that slices through the target gene. Experiments in cells with an inactivated form of Argonaute - which contributes only to the antiviral and not the gene regulation activity of RNAi - confirmed that they were observing an antiviral RNAi response. The observation that a viral protein called VP35, which is used by the Ebola and Marburg viruses to suppress RNAi, suggests that RNAi may also be active against those dangerous pathogens and other viruses that utilized RNA as their genetic code or in their replication cycle. "We now need to assess more directly the role of antiviral RNAi in human infectious diseases caused by RNA viruses - which include Ebola, West Nile and Zika along with influenza - and how harnessing or boosting the antiviral RNAi response could be used to reduce the severity of these infections," says Jeffrey, who is an assistant professor of Medicine at Harvard Medical School. "Bringing the expertise of Dr. Ding's team, which specializes in the RNAi biology of lower organisms, together with my group that specializes in mammalian immunology was a perfect match." The teams will continue to work together to investigate some of these questions. The co-lead authors of the Nature Microbiology paper are Yang Li, Jinfeng Lu and Shu-Wei Dong, University of California, Riverside; and Megha Basavappa, Massachusetts General Hospital. Additional co-authors are Alexander Cronkite, John Prior, Hans-Christian Reinecker and Sihem Cheloufi, MGH; Yanhong Han, Wan-Xiang Li and Fedor Karginov, UC Riverside; and Paul Hertzog, Hudson Institute of Medical Research, Victoria, Australia. Support for the study includes National Institutes of Health grants R01 AI107087, R01 AI52447 and R56 AI110579. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
News Article | December 5, 2016
Researchers discover long sought after mechanism in human cells that could help treat diseases caused by viruses, including influenza and Ebola RIVERSIDE, Calif. (http://www. ) -- A team of researchers, co-led by a University of California, Riverside professor, has found a long-sought-after mechanism in human cells that creates immunity to influenza A virus, which causes annual seasonal epidemics and occasional pandemics. The research, outlined in a paper published online today in the journal Nature Microbiology, could have broad implications on the immunological understanding of human diseases caused by RNA viruses including influenza, Ebola, West Nile, and Zika viruses. "This opens up a new way to understand how humans respond to viral infections and develop new methods to control viral infections," said Shou-Wei Ding, a professor of plant pathology and microbiology at UC Riverside, who is the co-corresponding author of the paper. The findings build on more than 20 years of research by Ding on antiviral RNA interference (RNAi), which involves an organism producing small interfering RNAs (siRNAs) to clear a virus. His initial research showed that RNAi is a common antiviral defense in plants, insects and nematodes and that viral infections in these organisms require active suppression of RNAi by specific viral proteins. That work led him to study RNAi as an antiviral defense in mammals. In a 2013 paper in the journal Science he outlined findings that show mice use RNAi to destroy viruses. But, it remained an open debate as to whether the same was true in humans. That open debate led Ding back to a key 2004 paper in which he described a new activity of a protein (non-structural protein 1, or NS1) in the influenza virus that can block the antiviral function of RNAi in fruit flies, a common model system used by scientists. In the current Nature Microbiology paper, the researchers demonstrated that human cells produce abundant siRNAs to target the influenza A virus when the viral NS1 is not active. They showed that the creation of viral siRNAs in infected human cells is mediated by an enzyme known as Dicer and is potently suppressed by both the NS1 protein of influenza A virus and a protein (virion protein 35, or VP35) found in Ebola and Marburg viruses. The researchers in the lab of the co-corresponding author, Kate L. Jeffrey, an investigator in the Massachusetts General Hospital gastrointestinal unit and an assistant professor of medicine at Harvard Medical School, further demonstrated that the infections of mature mammal cells by influenza A virus and other RNA viruses are inhibited naturally by RNAi, using mice cells specifically defective in RNAi. "Our studies show that the antiviral function of RNAi is conserved in mammals against distinct RNA viruses, suggesting an immediate need to assess the role of antiviral RNAi in human infectious diseases caused by RNA viruses, including Ebola, West Nile, and Zika viruses," Jeffrey said. The Nature Microbiology paper is called "Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells." In addition to Ding, the authors are: Yang Li (UC Riverside and Fudan University in China); Jinfeng Lu, Shuwei Dong, Yanhong Han, Wan-Xiang Li, and Fedor V. Karginov (all of UC Riverside); Megha Basavappa, D. Alexander Cronkite, John T. Prior, Hans-Christian Reinecker and Sihem Cheloufi (all of Harvard Medical School and/or Massachusetts General Hospital); and Paul Hertzog (of Hudson Institute of Medical Research in Australia.)
Young J.C.,Hudson Institute of Medical Research |
Young J.C.,Monash University |
Wakitani S.,Hudson Institute of Medical Research |
Wakitani S.,University of Miyazaki |
And 2 more authors.
Seminars in Cell and Developmental Biology | Year: 2015
The TGF-β ligand superfamily contains at least 40 members, many of which are produced and act within the mammalian testis to facilitate formation of sperm. Their progressive expression at key stages and in specific cell types determines the fertility of adult males, influencing testis development and controlling germline differentiation. BMPs are essential for the interactive instructions between multiple cell types in the early embryo that drive initial specification of gamete precursors. In the nascent foetal testis, several ligands including Nodal, TGF-βs, Activins and BMPs, serve as key masculinizing switches by regulating male germline pluripotency, somatic and germline proliferation, and testicular vascularization and architecture. In postnatal life, local production of these factors determine adult testis size by regulating Sertoli cell multiplication and differentiation, in addition to specifying germline differentiation and multiplication. Because TGF-β superfamily signaling is integral to testis formation, it affects processes that underlie testicular pathologies, including testicular cancer, and its potential to contribute to subfertility is beginning to be understood. © 2015 Elsevier Ltd.
Nsiah-Sefaa A.,Hudson Institute of Medical Research |
McKenzie M.,Monash University
Bioscience Reports | Year: 2016
Mitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP. Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis. © 2016 Authors.
Lee W.T.,Hudson Institute of Medical Research |
Lee W.T.,Monash University |
St John J.,Hudson Institute of Medical Research |
St John J.,Monash University
Annals of the New York Academy of Sciences | Year: 2015
Mitochondrial DNA (mtDNA) copy number is strictly regulated during development and tumorigenesis. Pluripotent stem cells and cancer stem-like cells use glycolysis for energy metabolism, as they possess low mtDNA copy number, which promotes cell proliferation. As pluripotent stem cells can differentiate into all cell types of the body, they establish the mtDNA set point during early development, maintaining mtDNA copy number at low levels but enabling differentiating cells to acquire the appropriate numbers of mtDNA copy to meet their specific demands for OXPHOS-derived ATP, as they become specialized cells. This process is mediated by changes to DNA methylation at exon 2 of the catalytic subunit of the mitochondrial-specific polymerase, POLGA. Cancer stem-like cells, however, are hypermethylated and maintain low mtDNA copy number, resulting in their dependence on aerobic glycolysis. Their hypermethylation at exon 2 of POLGA also promotes their multipotent state. As a result, cancer cells are unable to increase their mtDNA content and differentiate into specific lineages unless they are treated with DNA demethylation agents or partially depleted of their mtDNA. This review describes these processes in depth and argues that DNA methylation of POLGA is instrumental in the fate of pluripotent stem cells and cancer cells. © 2015 New York Academy of Sciences.
News Article | February 15, 2017
SAINT-PREX, Switzerland--(BUSINESS WIRE)--Ferring today announced the recipients of the 2016-2017 Ferring Innovation Grants program, an annual initiative of the Ferring Research Institute (FRI) which provides grants of up to $100,000 for early stage research. The program focuses on novel extracellular drug targets addressable with peptides or proteins within Ferring’s core therapeutic areas: reproductive health, gastroenterology, urology, and endocrinology. The 2016-2017 awardees and their research subjects are: Stuart Brierley - Flinders University, Australia Venom-derived NaV1.1 inhibitors as novel candidates for treating chronic visceral pain associated with IBS James Deane - Hudson Institute of Medical Research, Australia Investigating the requirement for Notch and Hedgehog signalling in the endometrial stem/progenitor populations that cause endometriosis Marie van Dijk - University of Amsterdam, Netherlands ELABELA as a potential biomarker and therapeutic for pre-eclampsia Florenta Kullmann - University of Pittsburgh, USA Artemin: a novel target for treatment of interstitial cystitis/bladder pain syndrome Mireille Lahoud - Monash University, Australia The development of Clec12A-ligands as a therapeutic approach to regulate gastrointestinal inflammation Padma Murthi - Monash University, Australia Investigating the role of novel peptide receptor as an effective target to improve placental function in preeclampsia Markus Muttenthaler - The University of Queensland, Australia Mapping the location and function of oxytocin and vasopressin receptors throughout the gut Rodrigo Pacheco – Fundación Ciencia & Vida and Universidad Andres Bello, Santiago, Chile Targeting heteromers formed by G-protein coupled receptors involved in the gut-homing of T-cells in inflammatory bowel diseases Aritro Sen – The University of Rochester, USA Regulation of AMH expression by GDF9+BMP15 and FSH during follicular development as a novel therapeutic option “We look forward to the outcomes of the research being carried out by our grant awardees,” said Keith James, President of FRI and Senior Vice President, Research and Development. “Ferring is committed to stimulating basic research, with the ultimate aim of developing innovative products that improve the lives of patients.” Applications for the 2017-2018 Ferring Innovation Grants programme will open in spring/summer 2017. For more information on this year’s program, visit www.ferring-research.com/ferring-grants. About Ferring Research Institute Inc Located in San Diego, California Ferring Research Institute Inc. (FRI) is the global peptide therapeutics research center for Ferring Pharmaceuticals. FRI is committed to building a portfolio of novel, innovative peptide-based drugs and biologicals to address the high unmet medical need for patients in our therapeutic areas of interest. For more detailed information please visit www.ferring-research.com. About Ferring Pharmaceuticals Headquartered in Switzerland, Ferring Pharmaceuticals is a research-driven, specialty biopharmaceutical group active in global markets. The company identifies, develops and markets innovative products in the areas of reproductive health, urology, gastroenterology, endocrinology and orthopaedics. Ferring has its own operating subsidiaries in nearly 60 countries and markets its products in 110 countries. To learn more about Ferring or its products please visit www.ferring.com.
Simpson E.,Hudson Institute of Medical Research |
Santen R.J.,University of Virginia
Journal of Molecular Endocrinology | Year: 2015
Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy’s had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists. © 2015 Society for Endocrinology.