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$5M grant to investigate relationship between gut and lung in respiratory disease

Australian researchers have been awarded a $5 million National Health and Medical Research Council (NHMRC) Synergy Grant for a project that will advance knowledge of the gut, microbiomes, metabolites and diet, and their role in both causing and potentially treating inflammatory respiratory diseases, particularly chronic obstructive pulmonary disease (COPD).

A respiratory disease also known as emphysema, COPD is the third leading cause of illness and death worldwide.

Involving investigators from leading medical research organisations and universities, the project will explore ways in which microbiomes, metabolites and immunity in the gut can be therapeutically manipulated to treat COPD.

Chief Investigator of the project, Professor Phil Hansbro (pictured), Director, Centenary UTS Centre for Inflammation (a joint initiative between the Centenary Institute and University of Technology Sydney) said COPD and lung diseases are enormous clinical issues and effective treatments are urgently needed.

“Most respiratory disease studies focus predominantly on the lung. We know, however, that there is microbial and immune crosstalk between the gut and the lungs. Gut diseases induce lung inflammation and are linked to COPD and asthma, and vice versa. New approaches that manipulate gut microbiomes have enormous potential as new therapies for lung diseases,” said Professor Hansbro.

The project will be led by three world-renowned senior investigators in addition to Professor Hansbro. They are Professor Emad El-Omar (UNSW Sydney), Professor Lisa Wood (The University of Newcastle) and Professor Meg Jardine (The University of Sydney).

“Such an ambitious project requires expertise in respiratory disease, gut disease, microbiology, immunology, nutrition and dietetics, clinical studies and trials, engineering, bioinformatics, statistics and multi-omics. We have brought together a top-class team with expertise across a diverse set of research disciplines,” said Professor Hansbro.

Stage one of the project will investigate the physiological linkages within the gut-lung axis–involving organ, microbe, metabolite and immune response interactions. The project will then determine ways in which the gut microbiome can be modulated as potential new therapies for COPD. Treatments could include the ingestion of certain microbes, antibiotics or specifically modified diets. These will then go into clinical trials and the roles of microbiomes and the metabolites that they produce will be defined.

Professor El-Omar, UNSW Microbiome Research Centre said, “This Synergy Grant is a great opportunity to deliver translational benefit to millions of COPD sufferers and demonstrates the emerging power of the microbiome revolution in medicine.”

“Projects like this will identify multiple potential treatments that need to be rigorously evaluated to determine their effectiveness in improving human health. We are excited to apply innovative trial solutions that can handle this complexity and allow us to systematically discover the most effective ways for improving health outcomes,” said Professor Jardine, Director of the University of Sydney’s NHMRC Clinical Trials Centre.

“Understanding the interplay between gut and lung health is critical to the development of new and innovative strategies for managing COPD. This project has the potential to lead to a paradigm shift in how we understand COPD,” said Professor Wood, University of Newcastle.

Supporting outstanding multidisciplinary teams of investigators working together, Synergy Grants are awarded by the NHMRC and look to answer major questions that cannot be answered by a single investigator.

New study to investigate lung treatment for COVID-19

Dr Matt Johansen from the Centenary UTS Centre for Inflammation is the successful recipient of the Kenyon Foundation Inflammation Award for 2021. The Award, valued at $20,000, will support Dr Johansen’s study into the development of a potential new treatment for COVID-19 aimed at reducing excessive inflammation in the lungs.

“There’s an urgent need to identify effective therapies that can be used to treat COVID-19 and significantly reduce mortality. Excessive lung inflammation is often the cause of severe disease and death in COVID-19,” said Dr Johansen.

In his study, Dr Johansen will be targeting the NLRP3 inflammasome, a master regulator of inflammation which drives a cascade of downstream inflammatory processes in severely affected COVID-19 patients. A known inhibitor of the NLRP3 inflammasome–a molecule known as MCC950–will be investigated for its efficacy as a potential COVID-19 treatment.

“MCC950 has already been shown to mitigate lung inflammation associated with respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD),” said Dr Johansen.

“It’s also been shown to be highly effective in alleviating virally-driven inflammation in influenza, suggesting it may also be an effective treatment for COVID-19.”

Dr Johansen’s study will be carried out at the Centenary Institute’s high-containment PC3 facility, of which there are only four in Australia that are properly equipped to complete this form of specialised SARS-CoV-2 medical research.

“I am incredibly humbled to have been selected for this Award which will financially assist our efforts to identify the most effective therapies for COVID-19,” said Dr Johansen.

“As governmental funding becomes increasingly difficult to acquire, philanthropic support from organisations such as the Kenyon Foundation are a significant boost that can promote fundamental scientific research that benefits us all.”

David Kenyon, Trustee of the Kenyon Foundation said, “We’re thrilled to be able to support Dr Johansen’s research that could form the basis for new therapies for the treatment of COVID-19 that has the potential to change lives.”

Equal first place for Alzheimer’s presentation

Honours student Andrew Quattrocchi has been awarded equal first place for his oral presentation on Alzheimer’s disease at the recent Australasian Conference of Undergraduate Research (ACUR).

A fourth year student at the University of Sydney, Andrew is currently completing his honours project in the Centenary Institute’s Vascular Biology Program led by Professor Jenny Gamble.

Andrew’s conference presentation was titled ‘Alzheimer’s Disease: Perivascular Macrophages and the Blood Brain Barrier’ and was focussed on a population of immune cells that surround and contact blood vessels, known as perivascular macrophages. These cells are thought to be involved in the early development of Alzheimer’s disease. 

“As the seventh leading cause of death globally and one of the most devastating neurological diseases in modern society, understanding the early changes that occur in Alzheimer’s disease is integral in developing targeted and effective treatments, something that still remains elusive,” said Mr Quattrocchi.

“It was extremely gratifying to be able to present my project to the wider scientific community and hearing the varied presentations of others was also a valuable and stimulating experience.”

Andrew was previously awarded two prizes at the Centenary Institute’s Summer Research Scholarship Program 2020/21 including first place for a presentation on Alzheimer’s disease. He is also exploring the possibility of undertaking a PhD, also under the supervision of Professor Gamble.

Orchid extract holds hope for prostate cancer treatment

Research led by the Centenary Institute has found that a compound extracted from a commonly cultivated orchid could be a potential new treatment option for prostate cancer.

The second most common form of cancer, prostate cancer is also the sixth highest cause of cancer-related mortality worldwide.

In the study, the researchers examined erianin, a natural bibenzyl compound, present in Dendrobium chrysotoxum, an orchid species native to Southeast Asia.

Erianin was found to have anti-tumour effects on both androgen-dependent (early-stage) and castration-resistant (advanced-stage) prostate cancer cells.  

“Early in their development, prostate cancers need androgens (male sex hormones), including testosterone, to grow,” explained Dr Yanfei (Jacob) Qi, Head of the Lipid Cell Biology Laboratory at the Centenary Institute and lead researcher on the study.

“Androgen deprivation therapy, also known as hormone therapy, aims to decrease androgen levels and can help slow or limit the cancer’s growth. When the prostate cancer stops responding to this treatment and continues to grow, the prostate cancer is at an advanced stage known as castration-resistant.”

Dr Qi said that the team’s research had shown that erianin elevated levels of a fatty acid called C16 ceramide inside the androgen-dependent prostate cancer cells. This caused the cells to die through a process called endoplasmic reticulum stress-associated cell death.

In contrast, erianin alone failed to elevate C16 ceramide levels in the castration-resistant prostate cancer cells. However, artificially increasing C16 ceramide in these cells, in conjunction with the use of erianin did result in successful cell death.

“Novel treatments for prostate cancer are urgently needed,” said Dr Qi.

“Up to twenty percent of patients receiving androgen deprivation therapy progress to advanced prostate cancer within five years.”

“We’ve shown that erianin could play an important role in the development of new medical drugs that are able to target both early and late-stage prostate cancers, potentially benefiting many patients and helping save lives.”

The study was published in the journal ‘Frontiers in Oncology’.

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Publication: Ceramide Regulates Anti-Tumor Mechanisms of Erianin in Androgen-Sensitive and Castration-Resistant Prostate Cancers.

Cell death discovery could lead to new treatment for COPD

Research shows that inhibiting necroptosis, a form of cell death, could be a novel therapeutic approach for treating chronic obstructive pulmonary disease (COPD), an inflammatory lung condition, also known as emphysema, that makes it difficult to breathe.

Published in the prestigious ‘American Journal of Respiratory and Critical Care Medicine’, the study by a team of Australian and Belgian researchers, revealed elevated levels of necroptosis in patients with COPD.

By inhibiting necroptosis activity, both in the lung tissue of COPD patients as well as in specialised COPD mouse models, the researchers found a significant reduction in chronic airway inflammation as well as damage to the lung.

Professor Phil Hansbro (pictured), Director of the Centenary UTS Centre for Inflammation who led the research team, said that necroptosis was a form of cell death known to drive tissue inflammation and destruction.

“Necroptosis, apoptosis and necrosis are all forms of cell death but they operate in distinctly different ways. Significantly, in necroptosis, a cell bursts, dispersing its contents into nearby tissues resulting in an immune and inflammation response.”

“Our research suggests that inhibiting necroptosis and preventing this inflammation response may be a new therapeutic approach to treating COPD,” said Professor Hansbro.

Joint first author on the study, Dr Zhe Lu, a researcher at the University of Newcastle, said that their study was the first of its type to be able to distinguish between the roles of necroptosis and apoptosis in COPD.

“Necroptosis is generally pro-inflammatory. Apoptosis, however, tends to be non-inflammatory as it’s a more ordered form of cell death–a cell self-degrades as opposed to bursting and there’s no leakage of cell contents. This may explain why, in our study, it’s the inhibition of necroptosis and not apoptosis that reduces lung damage and COPD associated inflammation,” said Dr Lu.

A debilitating respiratory condition and a leading cause of death worldwide, there are currently no treatments that halt or reverse the progression of COPD.

“Our research suggests that it is the type of cell death associated with COPD that is important and that the development of new drugs that can interfere or intervene in the necroptosis process could be a new targeted therapy for this common lung disease,” said Professor Hansbro.

The study was led by researchers from the Centenary Institute, University of Technology Sydney, University of Newcastle, Ghent University, Belgium and Ghent University Hospital, Belgium.

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Publication: Necroptosis Signalling Promotes Inflammation, Airway Remodelling and Emphysema in COPD. American Journal of Respiratory and Critical Care Medicine.

Boost to world-class melanoma research

World-class research into melanoma, the deadliest form of skin cancer, has been boosted with Dr Jessamy Tiffen, Head of the Centenary Institute’s ‘Melanoma Epigenetics Laboratory’, receiving a $447,000 project grant from Cancer Council NSW.

The grant will be used by Dr Tiffen to investigate new treatment approaches for patients with advanced stage melanoma.

Dr Tiffen said that new immunotherapies and targeted treatments provided hope for patients with advanced melanoma. However, for many patients, these treatments were ineffective or only worked for a limited time before the cancer developed resistance.

“Sadly, the majority of advanced melanoma patients will suffer relapse and die from the disease. There is an urgent need to identify new drugs for those individuals with no treatment options and to develop new drugs that can prevent recurrence of tumours,” said Dr Tiffen.

The focus of Dr Tiffen’s project will be the investigation of the histone methylation process which she believes plays an important role in driving treatment resistance in melanoma.

“Histone methylation involves protein activity around your DNA that can change the way your genes are expressed and can lead to changes in cell behaviour,” said Dr Tiffen.

“We believe that abnormal levels of histone methylation in both melanoma cells and dysfunctional immune cells could be causing resistance to treatment.”   

In the laboratory, Dr Tiffen will be testing different approaches to control histone methylation in melanoma. She hopes the research will lead to new drug treatments to stop melanoma growth or reverse the deadly treatment resistance.  

Professor Mathew Vadas AO, the Centenary Institute’s Executive Director, said the successful grant was a superb outcome for a vital project.

“The Centenary operates at the very forefront of this exciting aspect of melanoma research in Australia and I congratulate Dr Tiffen who has been awarded this important funding. I look forward to seeing the outcomes of this research which has the potential to help reduce the tragic loss of life associated with melanoma in this country.”

Further information on the Centenary Institute’s Melanoma Epigenetics Laboratory can be found here.

Gene discovery suggests new treatment approach for liver cancer

In a comprehensive analysis of human gene activation data, researchers from the Centenary Institute have discovered that the dipeptidyl peptidase-4 (DPP4) gene family is strongly implicated in the development of human hepatocellular carcinoma (HCC), the most common type of primary liver cancer.

Reported in the journal ‘Cancers’, the research suggests that the DPP4 gene family and the four enzymes that it contains should be further studied to support potential new therapeutic approaches to fighting tumours found in the liver.

“In this study we interrogated a number of publicly accessible human gene databases including The Cancer Genome Atlas to identify cancers associated with the DPP4 gene family,” said Dr Hui Emma Zhang, researcher in the Centenary Institute’s Liver Enzymes in Metabolism and Inflammation Program and co-senior author on the paper.

“We were focused on the four enzymes of the DPP4 gene family– DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). The role of the DPP9 enzyme was of particular interest as it hadn’t been studied previously with regard to liver cancer in humans,” Dr Zhang said.

Results from the data mining and subsequent analysis undertaken by the research team were revealing.

An association between high levels of the DPP9 enzyme and uterine and lung cancer was found suggesting that further investigatory work in both areas was required.

Elevated levels of DPP9, DPP4, FAP and DPP8 enzymes were also discovered in liver tumours and critically, were associated with poor survival rates in HCC patients.

“Our analysis indicates that high levels of all enzymes of the DPP4 family occur in liver cancers, which encourages us to target these enzymes as a possible new therapeutic approach to tackling the disease,” said Dr Zhang.

“With liver cancer incidence and mortality rates in Australia rapidly increasing new treatment options are urgently required both to improve and to save people’s lives.”

Over 2,000 Australians die each year from liver cancer. The five year survival rate for liver cancer is below 20%.

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Publication: DPP9: Comprehensive in silico analyses of loss of function gene variants and associated gene expression signatures in human hepatocellular carcinoma.

New method to assist fast-tracking of vaccines for pre-clinical tests

Scientists in Australia have developed a method for the rapid synthesis of safe vaccines, an approach that can be used to test vaccine strategies against novel pandemic pathogens such as SARS-CoV-2, the virus that causes COVID-19. 

Led by Professor Richard Payne at the University of Sydney and Professor Warwick Britton (pictured) at the Centenary Institute, the team has demonstrated application of the method with a new vaccine for use against tuberculosis (TB), which has generated a powerful protective immune response in mice. 

Researchers are keen to develop the vaccine strategy further to assist in the rapid pre-clinical testing of new vaccines, particularly for respiratory illnesses. 

“Tuberculosis infects 10 million and kills more than 1.4 million people every year,” said joint first author Dr Anneliese Ashhurst from the University of Sydney. “Historically, it is the leading cause of death worldwide from a single infectious agent. So far, a TB vaccine that is highly effective and safe to use in all populations has eluded medical science.” 

The only current vaccine for tuberculosis, the Bacille Calmette-Guerin vaccine, uses an injected live bacterium. It is effective in infants but has reduced effectiveness in adolescents and adults and poses significant health risks for immunocompromised patients, particularly for people living with HIV/AIDS. 

Protein-based vaccines have been shown to be very safe, but they must be mixed with enhancers, or adjuvants, to make them effective, which is not straightforward. 

Dr Ashhurst said: “The challenge is to ensure that our immune cells see both the protein and adjuvant simultaneously. To overcome this difficulty, for the first time we have developed a method that synthesises the protein with an attached adjuvant as a single molecule.” 

The vaccine strategy and synthetic technology could be deployed to rapidly generate new vaccines for pre-clinical testing for a range of diseases, the researchers say, including the respiratory pathogen that causes COVID-19. 

Their results are published today in the Proceedings of the National Academy of Sciences of the United States of America

HOW IT WORKS 

In order for vaccines to be effective, they need to stimulate behaviour in protective T-cells that allows them to recognise the pathogen as an antigen, or foreign body. In the case of tuberculosis, our immune system needs to respond quickly to the bacteria that causes TB – Mycobacterium tuberculosis – to reduce infection in lungs. 

Using the method developed by the Sydney scientists, an inhaled vaccine provides a low-dose immune-stimulating molecule – containing a synthesised bacterial protein attached directly to an adjuvant – to the immune cells in the lungs. 

A major hurdle overcome by the scientists was the difficulty in fusing hydrophobic (water-repellent) adjuvants with a water-soluble protein antigen. 

“We got around this problem of keeping hydrophobic and hydrophilic molecules together in a vaccine by developing a way to permanently bind the protein and adjuvant together as a single molecule using synthetic chemistry. Our approach overcomes the solubility problems faced by other methods,” said Professor Payne from the School of Chemistry and Deputy Director of the ARC Centre for Innovations in Peptide & Protein Science (CIPPS). 

The team says that synthesising an entire bacterial protein with attached adjuvant has not been achieved before. 

Professor Britton from the Tuberculosis Research Program at the Centenary Institute said: “As well as providing a rapid method to develop a range of vaccines for pre-clinical testing, we expect that this pulmonary vaccination approach will be particularly beneficial for protecting against respiratory diseases.” 

He said: “We hope that an inhaled vaccine for tuberculosis using a protein-based immunisation will allow us to develop a universal and safe approach to combatting this deadly disease.” 

The other major advantage with this method is that vaccines for a range of diseases can be developed rapidly and safely in the laboratory. 

“We don’t need to grow the actual pathogen in the lab to make the vaccine,” said Dr Ashhurst, who holds a joint position in the School of Chemistry and the School of Medical Sciences. “Using this new method, we can rapidly and safely synthesise highly pure vaccines in the lab and take them straight into animal models for pre-clinical testing.” 

Research paper: Synthetic protein conjugate vaccines provide protection against Mycobacterium tuberculosis in mice.

Read more about the Centenary Institute’s TB related medical research here.

Gut microbiome link to deadly lung disease

Research led by the Centenary Institute, the University of Technology Sydney and the University of Queensland has shown for the first time a link between chronic obstructive pulmonary disease (COPD), an often fatal lung condition, and the gut microbiome.

The findings, published in the high impact science journal ‘Nature Communications’, suggest that the gut may be helpful in diagnosing COPD and may also be a potential source of new therapeutic targets to help treat the chronic respiratory disorder.

“It’s already known that the lung microbiome is a contributing factor in COPD,” said Professor Phil Hansbro (pictured), senior author of the study and Director of the Centenary UTS Centre for Inflammation.

“We wanted to see if the gut environment was also somehow involved–to determine whether the gut could act as a reliable indicator of COPD or if it was connected in some way to the development of the disease.”

In the study, the researchers compared the microbiome and metabolite profiles of stool samples from COPD patients with healthy individuals. Revealed were significant differences between the two groups.

COPD patients exhibited increased levels of the bacteria Streptococcus and Lachnospiraceae in their stool samples. Also identified in individuals with COPD was a unique metabolite signature–formed by the chemical by-products of the metabolic process.

“Our research indicates that the gut of COPD patients is notably different from healthy individuals,” said first author on the paper Dr Kate Bowerman, University of Queensland.

“This suggests that stool sampling and analysis could be used to non-invasively diagnose and monitor for COPD,” she said.

The study’s researchers believe that the altered gut microbiome found in COPD patients could also support the gut as a potential target for new treatments.

“The ‘gut-lung axis’ describes the common immune system of the lung and gastrointestinal tract. This means that activity in the gut can impact activity in the lung. Our COPD findings suggest that the gut microbiome should now also be considered when looking for new therapeutic targets to help treat lung disease,” said Professor Hansbro.

COPD, a life threatening inflammatory disorder of the lungs, is the third most common cause of death globally. More than 3 million lives are lost every year to COPD.

Researchers involved in the study were affiliated with The University of Queensland, Hunter Medical Research Institute, University of Newcastle, The Prince Charles Hospital, Centenary Institute and University of Technology Sydney.

Publication: Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease.

Read more about our COPD related medical research here.

Professor Phil Hansbro on 60 Minutes

Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation has featured on the current affairs program 60 Minutes, explaining his critical research on bushfire smoke, its impact on the health of Australians and how his work could potentially lead to new prevention and treatment strategies.

“What we’re trying to do is to work out the important effects of bushfire smoke on your health and how it potentially affects different people in different ways– such as healthy people, people with asthma and emphysema, older people and those who are pregnant and their offspring,” said Professor Hansbro.

“Once we have this knowledge, we can then evaluate possible prevention and treatment measures including use of new anti-inflammatory drugs that may be able to help alleviate the effects of excessive smoke inhalation,” he said.

The full 60 Minutes story, titled ‘The Big Smoke’, can be accessed online (in two parts) via the Nine Network’s website.

A short video of Professor Hansbro on 60 Minutes can also be accessed on Twitter.