A research team led by Krembil Research Institute scientists has identified a new neuroprotective factor that has the potential to help people suffering from the common blinding disease glaucoma.
“This discovery provides hope that we can devise a new strategy for protecting the vision of glaucoma patients,” said Krembil Scientist Dr. Jeremy Sivak, who holds the Glaucoma Research Chair at the Donald K. Johnson Eye Institute at UHN and is Associate Professor at the University of Toronto.
Dr. Sivak’s research team was assisted by Dr. John Flanagan and Dr. Karsten Gronert of the University of California, Berkeley and the findings were published in the Journal of Clinical Investigation.
The team identified lipid molecule called LXB4 that protects neurons against the harmful effects of glaucoma in preclinical models. “We found that this tiny lipid molecule is normally present in healthy eyes and acts as a neuroprotective signal,” said Dr. Sivak. “Healthy eyes produce LXB4, but in diseased eyes its levels are reduced. We showed that by restoring LXB4 we can preserve injured nerve cells from dysfunction and death.”
Glaucoma is a progressive neurodegenerative disease of the optic nerve that is irreversible and can eventually lead to blindness. It affects more than 400,000 Canadians and 70 million people worldwide. Although there is no known cure, a key strategy to develop new treatments for glaucoma, and for other neurodegenerative conditions, is to find ways to preserve the survival of nerve cells.
“A particularly exciting part of this discovery is that we don’t think this effect is limited to glaucoma,” said Dr. Sivak. “This neuroprotection extends to the central nervous system and could be applicable to a host of other neurodegenerative diseases.”
Next steps for the research team include further investigation of the underlying mechanisms that control levels of the LXB4 molecule, and designing a practical method to restore levels of the molecule to treat disease. Researchers also plan to explore the potential application of this discovery to other conditions, such as Alzheimer’s Disease and Parkinson’s Disease.
Funding for this study was provided by the Canadian Institutes of Health Research, The Natural Sciences and Engineering Research Council of Canada, the National Institutes of Health and the Toronto General & Western Hospital Foundation.
Livne-Bar I, Wei J, Liu HH, Alqawlaq S, Won GJ, Tuccitto A, Gronert K, Flanagan JG, Sivak JM. Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury. J Clin Invest. 2017 Nov 6. pii: 77398. doi: 10.1172/JCI77398.
November marks the sixth anniversary of Techna, UHN’s youngest research institute. In that time Techna has grown its Technology Development Team to over 40 technical project managers, engineers, developers and more.
Techna was designed to accelerate the development of technology and to help deploy it into the healthcare system, and has had a number of successes in its short tenure. Partnerships with over 40 industry partners and the management of over 30 high-impact projects have helped Techna generate 10 patents, 29 licencing opportunities, 7 licensed products and 5 start-ups. Globally, Techna’s technologies and innovations now impact the treatment or management of over 3,000 patients daily.
In addition, Techna has moved toward self-sustainability with fee-for-service offerings to help develop and “productize” medical technology. Read more about their service offerings here.
Happy birthday, Techna!
The Techna Institute was established with the generous support of The Princess Margaret Cancer Foundation, FDC Foundation, Myron and Berna Garron and Agnico Eagle.
Maintaining work-life balance. Eating a healthy diet. Balance is something that our minds and bodies are constantly striving for.
For example, when the lungs are damaged by cigarette smoke or infections, the body sets to work, trying to repair the damage. Underlying this process is a type of cell known as the myofibroblast, which are recruited to the site of injury to orchestrate would-healing responses, including scar formation.
The problem is that, just as we sometimes fail at balancing our lifestyles, the body can get it wrong. In the case of repeated injury to the lung, myofibroblasts can become over-active; this promotes the formation of excessive scar tissue—so much so that the organ becomes inflexible, resulting in a serious condition known as pulmonary fibrosis. As fibrosis worsens, individuals with pulmonary fibrosis find it harder and harder to breathe and the transport of oxygen into the bloodstream becomes insufficient—causing respiratory failure and death.
It is not exactly known how myofibroblasts are activated to promote organ scarring. To address this issue, a team led by Krembil Senior Scientist Dr. Mohit Kapoor and co-lead investigators Dr. David Lagares and the late Dr. Andrew Tager (both from Harvard University) initiated a study to explore the molecular signals that activate myofibroblasts in people with pulmonary fibrosis.
In the study, the researchers compared lung myofibroblasts isolated from people with or without pulmonary fibrosis, and found that the level of Ephrin-B2, a protein on the surface of cells, was higher in myofibroblasts from fibrotic lungs. Using a series of experimental models, they discovered that an enzyme called ADAM10 causes part of Ephrin-B2 to be cleaved from the surface of the cell. The released piece, called sEphrin-B2, instructs myofibroblasts to migrate to the site of injury, generate scar tissue and promote fibrosis.
The team also found that administering sEphrin-B2 protein under the skin caused skin fibrosis, further implicating this molecule as a key player in the formation of excessive scar tissue. Moreover, by blocking the activity of ADAM10, they found that less sEphrin-B2 was released, resulting in reduced activation of myofibroblast cells and reduced fibrosis.
“Our study provides the first proof of concept that the ADAM10-sEphrin-B2 pathway drives organ fibrosis,” explains Dr. Lagares. Dr. Kapoor adds, “These results provide new targets for the development of therapies to prevent organ failure by preventing fibrosis—not only in the lungs and skin, but also in other tissues affected by fibrosis such as joints, the heart, the liver and the kidney.”
This work was supported by Université de Montréal, the American Thoracic Society Foundation, the Pulmonary Fibrosis Foundation, the Scleroderma Foundation, the National Institutes of Health, the Scleroderma Research Foundation and the Toronto General & Western Hospital Foundation.
Lagares D, Ghassemi-Kakroodi P, Tremblay C, Santos A, Probst CK, Franklin A, Santos DM, Grasberger P, Ahluwalia N, Montesi SB, Shea BS, Black KE, Knipe R, Blati M, Baron M, Wu B, Fahmi H, Gandhi R, Pardo A, Selman M, Wu J, Pelletier JP, Martel-Pelletier J, Tager AM, Kapoor M. ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis. Nat Med. 2017 Oct 23. doi: 10.1038/nm.4419.
UHN was ranked number one on the 2017 list of Canada’s Top 40 Research Hospitals, released by RE$EARCH Infosource Inc.
The annual rankings compare research hospitals across Canada according to their research funding data. Funds that were considered included grants, contributions and contracts from all internal and external government and non-government sources.
UHN research expenditures totaled $332 million in the 2016 fiscal year, a value that earned the UHN the top rank for the seventh year in a row. In comparison to last year, UHN research expenditure funding increased by 5%.
Within the “Large Hospitals” category (total hospital spending >$1B), UHN also led in terms of research hospital intensity, which is defined as the percent of research spending versus total hospital spending. Within the same category, UHN came in fourth in terms of research intensity (dollars spent per appointed researcher), with London Health Sciences Centre in the lead.
Other hospitals that ranked among the top five for total research expenditure included The Hospital for Sick Children in Toronto ($201.4M), McGill University Health Centre in Montreal ($178.8M), Hamilton Health Sciences ($171.4M) and the Provincial Health Services Authority in Vancouver ($161.9M).
To view the complete list of Canada’s Top 40 Research Hospitals, click here. To see the Spotlight on Hospital Research Activity within the large hospitals category, click here.
RE$EARCH Infosource Inc. reports on research across Canada, and releases other annual lists, including the Top 50 Research Universities and Top 50 Research Colleges.
Rick Hansen is a Canadian icon who changed our perception of spinal cord injury (SCI). As a teenager, he sustained an SCI that paralyzed him below the waist. Despite his disability, he embarked on a trek across the world in his wheelchair. He performed this amazing feat as part of his ‘Man in Motion World Tour’ to raise funds for SCI research and promote the potential of all people living with disabilities.
The spinal cord consists of a thin column of nerve tissue that extends from the base of the brain to the lower back. It serves as the main pathway through which the brain and the rest of the body communicate. This two-way communication is dependent on the millions of nerve cells and the fibers that extend from them and comprise the spinal cord. Damage to the spinal cord can kill nerve cells or impair their function, leading to pain, paralysis and loss of sensation in different parts of the body. Presently, there are no treatments to repair the damage from SCI.
Researchers have shown that a molecule known as RGMa is involved in nerve tissue injury. RGMa is produced in nerve tissue, prevents the growth of damaged nerve fibers and is detected at high levels in tissues affected by diseases such as multiple sclerosis and Alzheimer disease.
In light of these observations, a team of Krembil researchers examined the potential role of RGMa in SCI. This team was led by Drs. Charles Tator, Philippe Monnier and Andrea Mothe.
The researchers found that damaged spinal cord tissue from patients and an experimental model of SCI contained high levels of RGMa, suggesting that the molecule was produced in response to damage. Importantly, they showed that inhibiting RGMa activity in the SCI model produced several positive effects: not only did it promote the survival of nerve cells and the growth of their fibers near the site of injury, but it also improved movement, coordination and mobility. Moreover, the inhibition of RGMa also alleviated the pain that typically follows SCI.
These findings highlight the therapeutic potential of targeting RGMa to promote recovery after SCI. If RGMa inhibition continues to produce promising results in the lab, clinical trials will be conducted to establish whether it benefits patients with SCI.
This work was supported by the Rick Hansen Institute, the Canadian Institutes of Health Research, AbbVie, Spinal Cord Injury Ontario and the Toronto General & Western Hospital Foundation.
Mothe AJ, Tassew NG, Shabanzadeh AP, Penheiro R, Vigouroux RJ, Huang L, Grinnell C, Cui YF, Fung E, Monnier PP, Mueller BK, Tator CH. RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury. Sci Rep. 2017 Sep 5. doi: 10.1038/s41598-017-10987-7.