Dr. Athanasios Didangelos is a Rosetrees Trust-funded principal investigator at the University of Leicester, working in the Mayer IgA Nephropathy Laboratory led by Professor Jon Barratt. Their new publication in the Journal of Autoimmunity has identified a new urine marker in IgA Nephropathy (IgAN) known as PEBP4. The protein was found by deep-screening of the urinary proteome by shotgun mass-spectrometry proteomics.
Athanasios Didangelos and Scott
IgAN (a very common kidney disease) can lead to chronic kidney damage and renal failure. A substantial proportion of patients (~20%) end up needing expensive and burdensome dialysis as well as kidney transplants. It is therefore important to identify potential disease markers and/or soluble bioactive factors in IgAN to support early diagnosis and new treatment opportunities. Currently, there are no drugs that can treat IgAN and no biomarkers that can predict disease outcomes.
With the discovery of PEBP4, Dr. Didangelos and his team showed that its concentration is increased in serum and urine of IgAN patients. More importantly, the levels of the soluble protein in urine and serum appeared to positively correlate with the extent of kidney damage in IgAN patients.
The next steps of this research would require further investigation into the role of PEBP4 in kidney pathology. One particular area or interest, is the potential relationship of PEBP4 with B-cells (major disease effectors in IgAN) as well as its likely interplay with a key inflammatory factor named interferon gamma. Importantly, PEBP4 might be involved in inflammatory mechanisms in other diseased organs and tissues.
IgAN is a chronic and progressive disease that affects the kidneys of many thousands of patients in the UK and worldwide. Since there are no treatments for IgAN, these patients have to live for years with a condition that affects a major human organ as well as the devastating uncertainty of whether they will need dialysis or kidney transplantation in the future. I have met multiple IgAN patients and have understood the need to identify new treatment options and clinical prognostic tools for the disease. PEBP4 is a new soluble bioactive candidate that gives us the opportunity to investigate new treatment avenues, specifically targeting important inflammatory cell types (B-cells) and unexplored pathological pathways. Together with Professor Jon Barratt, our work at the Mayer IgA Nephropathy Laboratory, aims to identify new molecules and disease pathways that we can target in much needed future therapies.
Written by: Rebecca Downing and Dr. Athanasios Didangelos
Soaad Soboh and Sergei Butenko
Recent Rosetrees Trust-funded research published in Nature Communications has highlighted the therapeutic potential of IFN-β in chronic and non-resolving inﬂammation, as well as ﬁbrotic disorders and wound repair. Specifically, IFN-β has been identified as a macrophage-derived multi-pronged effector in resolving inﬂammation. Dr. Amiram Ariel is funded by Rosetrees, and is the researcher who led this investigation, which was carried out at the University of Haifa.
Interestingly, this research also develops our understanding of IFN-β in anti-bacterial defence. As previously there had been considerable efforts into understanding its role in host response to viruses primarily. Therefore, Dr. Ariel and his collaborator, Prof. Filep from the University of Montreal, have not only identified the therapeutic potential of IFN-β in certain inflammatory diseases, there has been additional insight into the role of IFN-β in enhancing the eradication of bacteria during pneumonia.
Dr. Amiram Ariel
Dr. Ariel explained: “Enhancing the resolution of inflammation is a novel approach in eradicating chronic inflammatory, autoimmune and fibrotic disorders, and our studies reveal IFN-β as a potential new therapy in this arena”. The groups of Dr. Ariel and Prof. Filep discovered IFN-β is produced by specialised immune cells called macrophages following their uptake of dead neutrophils during the resolution of inflammation. IFN-β, in turn, enhances bacterial clearance from infected tissues, and expedites apoptotic death of inflammatory neutrophils, the uptake of apoptotic neutrophils by macrophages and the consequent reprogramming of these macrophages to resolution-promoting macrophages. Thus, IFN-β seems amenable in limiting unnecessary prolonged inflammation without risking the host with immune insufficiency and pathogen persistence, and harnessing its direct use or finding compounds that will enhance its production by macrophages for therapeutics purposes seems like a promising approach in the treatment of inflammatory and fibrotic disorders.
Written by: Rebecca Downing and Dr. Amiram Ariel
Macrophages that have engulfed apoptotic cells in culture.
Professor Chaozong Liu is leading a Rosetrees Trust-funded project, with postdoctoral research associate Dr. Maryam Tamaddon, to investigate a tissue engineering approach for the treatment of cartilage damage, as a result of repetitive injuries or osteoarthritis.
Based at UCL Institute of Musculoskeletal and Orthopaedic Sciences, the team have already developed a novel ex vivo bone plug model for evaluating scaffold technology in order to speed up translation of this technology into clinical practice. They have also demonstrated improved mechanical and biological parameters in various model systems, both in vitro and in vivo.
Dr. Maryam Tamaddon
The team have recently received ethical approval to access young patients’ tissue for use in their project. “This is an important step because there is variability between children and adults for this type of study, and children are currently under-investigated. This allows the researchers to understand the osteoarthritis development at early stage”, as quoted by Dr. Maryam Tamaddon.
Significantly, a Phase I clinical trial has been agreed to start in October 2019, with a cohort of 20 patients. This will take place at the Royal National Orthopaedic Hospital, NHS Trust, for patients with knee joint cartilage damage. Safety is being considered as the primary outcome. The results from this trial will be relevant to clinicians, because this will offer a new treatment option for treatment of cartilage damage.
Professor Chaozong Liu
Once the Phase I clinical trial has begun, this will facilitate subsequent running of other trials in parallel and recruitment of more patients.
Professor Chaozong Liu from University College London, who is leading this research, commented, “We have demonstrated that the novel Bone Plug Model, developed under a Rosetrees Trust award, is able to provide more relevant human tissue-scaffold interactions, and speed up the translation of novel technology into clinical practice. We are very happy with the achievement and very grateful for Rosetrees Trust for supporting our work.”
Written by: Rebecca Downing and Professor Chaozong Liu
Dr. Williams-Gray is a Rosetrees Trust-funded researcher based at the University of Cambridge, who is leading a team that is currently investigating the role of Toll-like receptors in brain inflammation and disease progression in Parkinson’s disease and its associated dementia. The team are using human post-mortem tissue from patients with Parkinson’s to explore the relationship between pathological changes and clinical course of the disease. In addition, they are using a novel laboratory-based model of Parkinson’s disease which will allow them to determine how Toll-like receptor blocking drugs will affect the inflammatory response and consequent nerve cell damage.
A recent review of Toll-like receptors in Parkinson’s disease and alpha-synucleinopathies, published by Dr. Caroline Williams-Gray and her team, supports the idea that these receptors may have potential as therapeutic targets. In their review, they have highlighted that there is increased interest in using treatments aimed at either preventing or stopping brain inflammation in these diseases.
“Toll-like receptors are critical for the activation of immune cells and inflammation in the brain – and evidence that they play a role in Parkinson’s disease is accumulating.” – Antonina Kouli (Postdoctoral Research Associate, University of Cambridge)
Dr. Williams-Gray’s group also studies immune activation and inflammation in the blood in Parkinson’s disease patients. This work has implicated changes in immune cell types and function in Parkinson’s (Williams-Gray et al., 2018; Wijeyekoon et al., 2018; Scott et al., 2018), and has shown that patients who have more inflammation in the blood when they are diagnosed have more rapid progression of their disease (Williams-Gray et al., 2016). Their work to date on human post-mortem tissue confirms brain inflammation and specifically implicates Toll-like receptors in Parkinson’s disease and these findings will enhance our understanding of the neuropathological basis of Parkinson’s disease dementia, once published. Work is ongoing on the laboratory model, and due to complete in the next few months. If successful, this may pave the way for clinical trials of Toll-like receptor blocking drugs for use in the treatment of Parkinson’s disease.
“There is an urgent need to develop treatments that can halt or slow down the progression of Parkinson’s disease, as well as other neurodegenerative conditions which cause dementia. Suppressing brain inflammation is an exciting potential strategy which may be relevant to many of these diseases, and Toll-like receptors may provide a specific therapeutic target.” – Caroline Williams-Gray (Senior Clinical Research Associate, University of Cambridge & Honorary Consultant Neurologist, Cambridge University Hospitals NHS Foundation Trust)
Written by: Rebecca Downing and Dr. Caroline Williams-Gray
Dr. Tina Chowdhury is a Rosetrees Trust-funded researcher, leading a team of scientists in the field of regenerative medicine. She is based at the Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, where she also plays an active role in science communication and public engagement alongside her academic roles.
Having recently given an exciting talk about saving babies’ lives, Dr. Chowdhury continues to inspire the next generation promoting subjects in STEAMM to young people at schools. The talk was chaired by Professor Brian Cox (OBE) who joined Dr. Chowdhury for a Question and Answer session. A short summary of her talk can be found on the Queen Mary University of London website.
Talk about saving babies’ lives inspires young people to become bioengineers
Dr. Chowdhury and her team, including Professor Anna David at UCL and Dr. David Barrett, have recently published the Rosetrees Trust-funded findings in Scientific Reports. This work was specifically about repairing fetal membranes to prevent preterm birth. A brief overview of the findings, can be found here on the Queen Mary University of London website.
You can also listen to the podcast from 12.15 where Tina was interviewed by Dr. Chris Smith, Naked Scientists.
This project has been very successful, generating five publications and one book chapter in total, as well as winning seven awards and prizes for the research. A project grant was awarded to Dr. Chowdhury and her collaborators from Great Ormond Street Hospital and Sparks children’s charities for the continuation of this work. Dr. Barrett achieved his PhD in March 2018, and worked as a Post-Doctoral Researcher funded by Sparks. Dr. Babatunde Okesola joined Tina’s team last month and is designing materials with nanotechnology to seal tears in fetal membrane defects.
In another Rosetrees Trust-funded project, Dr. Chowdhury and her team investigated a tissue engineering approach to repair defects in the windpipe of the unborn baby, using fetal stem cells. Studies from the PhD student working on this project, James Taylor, will contribute to a publication. This work will be important because of the particular emphasis on the novelty of using fetal-derived stem cells to generate chondrocytes.
Little Heartbeats is raising awareness for PPROM.
Dr. Chowdhury and her team are also receiving ongoing Rosetrees Trust funding for a project to heal fetal membrane defects and avoid preterm birth. This project combines technology in material chemistry, mechanobiology, biomechanics and imaging, to test therapies with fetal-on-a-chip mechanical models. The data obtained is in the early stages of this work and will be presented at the 23rd International Society for Prenatal Diagnosis and Therapy, Singapore in September 2019 and has been nominated for an Early Investigator award. This is a great opportunity for the PhD student working on this project, Eleni Costa, to showcase the latest findings from the team to leading experts in the field.
Here are a few words from Dr. Chowdhury: “In 2018, we established the Fetal Membrane Repair Network with a global community of scientists, clinicians, engineers, advocacy groups (Little Heartbeats) and children charities (Sparks, GOSH) to discuss ways to improve healing of the membranes after surgery or after the membranes rupture spontaneously. By working collaboratively with a multi-disciplinary team and by raising awareness about PPROM, we plan to develop a new clinical intervention that will improve healing, delay delivery and prevent preterm birth. We are very grateful to the Rosetrees Trust for supporting our research team and for inspiring the next generation of bioengineers.”
Written by: Rebecca Downing and Dr. Tina Chowdhury
Antimicrobial resistance is recognised as the one of the gravest threats to global human health and is expected to kill more people than cancer by 2050. Therefore, new antibiotics are crucial. Rosetrees-funded research led by Dr. Ishwar Singh at Lincoln University has made, and continues to make, a significant contribution to the discovery and development of novel antibiotics. Currently, Dr. Singh is leading one of several teams around the world, in the fight against resistance, by developing teixobactin. This work was recently highlighted in the Guardian.
Dr. Ishwar Singh
Dr. Singh explained: “Antimicrobial resistance is spreading faster than the introduction of new antibiotics, which means there are major concerns about a possible health crisis. To tackle this global challenge, we are at the forefront of the development of 21st century antibiotics, teixobactins which kill multi-drug resistant bacterial pathogens such as MRSA.”
Teixobactin is exciting because it is a recently discovered natural compound, belonging to a new class of antibiotics and kills multi-drug resistant bacterial pathogens without detectable resistance. In his research, Dr. Singh aims to develop a library of simplified highly potent teixobactins to overcome the unmet clinical challenges in antimicrobial resistance. To achieve this, Dr. Singh will need to prepare, evaluate and gain mechanistic insights into the teixobactins he develops during this project.
In the long-term, this project can ultimately contribute to providing a new class of 21st century, clinically relevant, licensed antibiotics.
Written by: Rebecca Downing and Dr. Ishwar Singh