It may seem like your bones are stable and unchanging, but it may surprise you to learn that they are constantly being remodelled. Cells called osteoclasts and osteoblasts respectively erode and rebuild bone in a continuous manner—renewing one tenth of the adult skeleton each year.
Because bones provide the support structure for the entire body, the disruption of bone development and growth can lead to serious consequences. For example, those with cleidocranial dysplasia are born with genetic mutations that lead to bone malformations, including short stature, underdeveloped collarbones and holes in the skull. The genetic causes are not known in up to 40 per cent of people with this disease, but a new study by PM Senior Scientist Dr. Robert Rottapel identifies a novel genetic candidate.
Using an experimental model, Dr. Rottapel and his research team found that deletion of a gene known as Rnf146 in osteoblasts leads to short stature and malformation of the collarbones and skull—all features of cleidocranial dysplasia. The researchers dug deeper and found that loss of Rnf146 turned off a bone development pathway that involves the proteins Wnt and beta-catenin.
They also found that loss of Rnf146 turned off the production of the hormone osteocalcin, which normally promotes the release of insulin and signals the body to use sugar (glucose) for energy. The absence of osteocalcin in turn resulted in glucose intolerance, a pre-diabetic state that is characterized by an inability to use glucose as an energy source and a buildup of glucose in the blood.
"Our study has revealed a previously unknown molecular switch that controls bone development and metabolism," explains Dr. Rottapel. "Furthermore, our findings suggest that people with cleidocranial dysplasia may be at risk of developing metabolic diseases such as diabetes. Future studies are required to explore this link and potential therapeutics."
This work was supported by the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, the Japan Society for the Promotion of Science, the Japan Rheumatism Foundation, the Sumitomo Life Social Welfare Services Foundation, the Nakayama Science Foundation and The Princess Margaret Cancer Foundation.
Matsumoto Y, La Rose J, Lim M, Adissu HA, Law N, Mao X, Cong F, Mera P, Karsenty G, Goltzman D, Changoor A, Zhang L, Stajkowski M, Grynpas MD, Bergmann C, Rottapel R. Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism. J Clin Invest. 2017 Jun 30. doi: 10.1172/JCI92233.
Dr. Jekyll and Mr. Hyde are famous literary characters that behaved very differently: one was kind and sociable and the other evil and self-indulgent. Eventually, we learn that they are one and the same person.
TGHRI Scientist Dr. Jason Fish has demonstrated that, like Jekyll and Hyde, a molecule known as microRNA-146a (miR-146a) can play two different roles in heart disease, depending on the context. miR-146a is produced in many different types of cells throughout the body, including cells that comprise the immune and cardiovascular systems.
Heart disease is the leading cause of death worldwide. It is characterized by the accumulation of fatty deposits, known as plaques, in the blood vessels that supply the heart with oxygenated blood. Over a long period of time, these plaques can build-up until they completely block the vessels, preventing the heart from receiving enough blood to keep it pumping.
Although researchers do not fully understand the molecular mechanisms that trigger and promote plaque formation—a process known as atherosclerosis—they suspect that miR-146a could be involved. Previous clinical studies have detected high levels of miR-146a in atherosclerosis plaques. Moreover, modifications to the structure of the miR-146a molecule can alter a person’s risk of developing heart disease.
The recent study, led by Dr. Fish and his PhD student Henry Cheng, examined the effects of depleting miR-146a in different types of cells in an experimental model of atherosclerosis. The researchers found that when miR-146a is depleted from bone marrow, harmful plaque production was reduced; however, miR-146a’s absence also compromised the bone marrow’s activity.
Depleting miR-146a did not always reduce plaque formation. In fact, when depleted from the cells that line blood vessels miR-146a had the opposite effect: it promoted plaques.
These findings highlight the importance of cell context within biological systems: a molecule’s role in disease can depend on where it functions. Moreover, they reveal that augmenting levels of miR-146a in certain cells could represent a new strategy for preventing heart disease.
This work was supported by the Canadian Institutes of Health Research; the Heart & Stroke Foundation of Canada; the Canada Foundation for Innovation; the Ontario Ministry of Research, Innovation and Science; the Heart & Stroke Richard Lewar Centre of Excellence in Cardiovascular Research; the Canadian Vascular Network; and the Toronto General & Western Hospital Foundation. JE Fish holds a Tier 2 Canada Research Chair in in Vascular Cell and Molecular Biology.
Cheng HS, Besla R, Li A, Chen Z, Shikatani EA, Nazari-Jahantigh M, Hammoutène A, Nguyen MA, Geoffrion M, Cai L, Khyzha N, Li T, MacParland SA, Husain M, Cybulsky MI, Boulanger CM, Temel RE, Schober A, Rayner KJ, Robbins C, Fish JE. Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a. Circ Res. 2017 Jun 21. doi: 10.1161/CIRCRESAHA.116.310529.
UHN researchers were awarded a total of $1.14M from the Canada Foundation for Innovation (CFI) to purchase key research equipment.
The funds were awarded through CFI’s John R. Evans Leaders Fund, which is designed to help institutions attract and retain the best and brightest researchers from around the world.
The funds will enable the acquisition of equipment needed to implement the following research programs:
Target screening and immuno-profiling platform for difficult to treat cancers
Lead researchers: Drs. Mathieu Lupien, Pamela Ohashi, Bradly Wouters
Translational research pipeline for retinal and neurodegenerative diseases
Lead researchers: Drs. Philippe Monnier, Valerie Wallace, Michael Tymianski
These projects were among 220 new infrastructure projects announced at Laurentian University in Sudbury, Ontario on August 15, 2017. In total, these investments sum to over $52M distributed across 51 Canadian universities, including $5.7M at the University of Toronto.
Commenting on the announcement, Canada’s Minister of Science Kirsty Duncan said, “Our scientists need the best tools and equipment for ground-breaking research and discovery, and we are committed to ensuring they have them.”
“Their successes will lead to an improved economy and will fuel an active research community here in Canada and internationally.”
Congratulations to the six UHN researchers involved and to CFI for their continued support.
In 2014, actress and singer Selena Gomez took some time out of the spotlight. While rumours swirled, it turned out that the hiatus was required so she could receive treatment for a disease known as lupus.
Millions of individuals worldwide, mostly women between the ages of 15 to 44, struggle with lupus. It is an autoimmune disease, meaning that the body’s immune system goes into overdrive—attacking and causing extensive damage to healthy tissue.
B cells, named for their production in bone marrow, are one of the body’s most important immune cells; they release specialized proteins (ie, antibodies) that protect the body from invaders such as viruses or bacteria. However, it is believed that they also play a critical role in initiating lupus by producing ‘harmful’ antibodies that tell the immune system to attack healthy cells.
Krembil Senior Scientist Dr. Joan Wither and her team have been using experimental models of lupus to uncover how and why B cells betray the body and incite the immune system to attack healthy cells.
In a recent study, the researchers tracked B cell antibody production using an experimental model in which B cells were forced to express a specific genetic code that induced lupus-like symptoms. The team discovered that this genetic code not only increased the proportion of antibody-producing B cells, but also the levels of antibody production.
The code also increased the proportions of another type of immune cell (T follicular helper cell) that is known to enhance the growth of antibody-producing B cells. As the proportion of these T follicular helper cells increased, the proportion of B cells grew, and likewise, antibody production was augmented. These changes created an environment where the immune system was primed to attack healthy tissues.
“Although several studies have shown that defects in B and T cell populations contribute to antibody production, it still is not clear exactly how this occurs in the context of lupus,” says Dr. Wither. “Our data reveal that changes in the proportion of T follicular helper cells may play a role in this process by enhancing the growth of the types of B cells that end up betraying the body and causing lupus.”
This work was supported by the Canadian Institutes of Health Research, and the Toronto General & Western Hospital Foundation.
Chang NH, Manion KP, Loh C, Pau E, Baglaenko Y, Wither JE. Multiple tolerance defects contribute to the breach of B cell tolerance in New Zealand Black chromosome 1 congenic mice. PLoS One. 2017 Jun 19;12(6):e0179506. doi:10.1371/journal.pone.0179506.
The Krembil Research Institute has partnered with The Globe and Mail to release a magazine series highlighting Krembil research advancements. The second magazine in the series was distributed to Globe and Mail subscribers across Canada on June 27, 2017 and focuses on success stories from Krembil’s Donald K. Johnson Eye Institute (read the full issue online).
“In recent years, we’ve assembled a top-notch team of research scientists who are committed to finding answers to fundamental questions about the retina, the brain and disease function,” says Dr. Valerie Wallace, Co-Director of Krembil’s Donald K. Johnson Eye Institute, along with Dr. Robert Devenyi.
Stories within the Globe and Mail ‘Vision’ magazine highlight the significant advancements that Krembil researchers have made in recent years, and the new frontiers that they are exploring to better diagnose diseases of the eye and restore vision. These stories are summarized below:
· Dr. Philippe Monnier is developing therapies that can prevent cell death, reverse nerve damage and cure vision loss, as well as other diseases such as multiple sclerosis and stroke.
· Dr. Efrem Mandelcorn is adapting a simple eye test to facilitate the early diagnosis of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, before people have symptoms.
· Dr. Valerie Wallace is searching for a way to use transplanted cells to restore vision.
· Dr. Robert Devenyi is pioneering a new vision-saving method for people with retinal detachment—an emergency condition in which the tissue layer at the back of the eye is compromised.
· Dr. Jeremy Sivak is looking for ways to treat glaucoma, a group of conditions that are caused by damage to the optic nerve (ie, the major connection between the eye and the brain).
· Drs. David Rootman and Allan Slomovic are bringing back patients’ vision by improving and implementing innovative surgical techniques.
· The late Dr. Martin Steinbach will be remembered for his leading contributions to vision research in Canada, including his most recent scientific endeavour: using virtual reality technology to detect the early signs of glaucoma, before eye damage occurs.
· Dr. Michael Brent is finding ways to break barriers and make it easier for people with diabetes to get regular eye exams.
Also in the magazine, vision research benefactor Donald K. Johnson explains the importance of private sector donations to “…help research organizations go from being good to being great.”
“There are many exciting stories of progress and success emerging from our laboratories,” explains Krembil Director Dr. Donald Weaver. “Some of these stories are told in this magazine. This is only a sampling of what we do and what we are capable of.”
We do it several times a day. We do it quickly. Some people even do it while crossing the street.
Texting is an everyday activity that we do effortlessly and take for granted. However, for a person affected by Parkinson disease (PD), it is challenging and can become impossible.
PD is a progressive neurological disorder characterized by slowed movements, tremors, stiff muscles and impaired balance. Its symptoms are caused by the gradual loss of brain cells, especially those producing the chemical dopamine, which is essential for producing smooth well-controlled movements.
In 2013, a team of researchers led by TGHRI Senior Scientist Dr. Anne Bassett found that PD occurs more frequently in people with 22q11.2 deletion syndrome than those without the syndrome. The syndrome is caused by a genetic alteration that can produce a wide variety of symptoms such as heart and palate abnormalities, learning disabilities, schizophrenia and seizures.
Continuing this thread of work, Dr. Bassett and her colleagues recently examined the signs and symptoms of PD in a group of adults with 22q11.2 deletion syndrome and in healthy participants.
The researchers found that several symptoms of PD—such as slow movements, tremors and reduced balance—were much more common in the 22q11.2 deletion group than in healthy participants. The brain scans from a patient with 22q11.2 deletion syndrome and full-blown PD showed the expected loss of dopamine-producing cells. However, researchers found the opposite in the 22q11.2 deletion group displaying only a few symptoms of PD: these participants had significantly more dopamine-producing brain cells than healthy participants.
“We speculate that too much dopamine, which may be harmful to brain cells, could increase the risk of developing not only PD, but also some of the mental illnesses that commonly occur in 22q11.2 deletion syndrome”, said Dr. Bassett of the findings.
This work demonstrates that studying 22q11.2 deletion syndrome can help to reveal the mechanisms underpinning PD and related movement disorders, as well as other complex brain diseases. Future research will shed light on these mechanisms by studying experimental models and patients over a longer period of time, starting before the appearance of PD symptoms and continuing to full-blown disease.
This work was supported by the Canadian Institutes of Health Research, Brain Canada, the National Commission for Scientific and Technological Research (Chile) and the Toronto General & Western Hospital Foundation. AS Bassett holds a Tier 1 Canada Research Chair in Schizophrenia Genetics and Genomic Disorders. AP Strafella holds a Tier 2 Canada Research Chair in Movement Disorders and Neuroimaging. AE Lang holds the Jack Clark Chair for Parkinson’s Disease Research and the Lily Safra Chair in Movement Disorders at the Toronto Western Hospital. AS Bassett holds the Dalglish Chair in 22q11.2 Deletion Syndrome at the Toronto General Hospital.
Butcher NJ, Marras C, Pondal M, Rusjan P, Boot E, Christopher L, Repetto GM, Fritsch R, Chow EW, Masellis M, Strafella AP, Lang AE, Bassett AS. Neuroimaging and clinical features in adults with a 22q11.2 deletion at risk of Parkinson's disease. Brain. 2017 Mar 24. doi: 10.1093/brain/awx053.
The Krembil Research Institute has embarked on a mission to achieve operational excellence, and focus and augment research activity. As part of this endeavour, Krembil Senior Scientist Dr. Mohit Kapoor has been named as the inaugural Research Director for the arthritis research group.
The mission began with the merging of vision research and clinical programs into one institute, the Donald K. Johnson Eye Institute, under the combined leadership of Co-Directors, Drs. Valerie Wallace and Robert Devenyi. This collaborative effort has already resulted in renewed direction for the vision science research group at Krembil. The next step is to establish research priorities for the arthritis research group.
“It is essential that we establish research priorities that position us for the future,” says Krembil Director Dr. Donald Weaver. “Building harmony between our fundamental and clinical science pursuits will foster collaboration amongst the various medical and surgical disciplines, leading to novel and important research questions, and facilitating the transfer of basic research advancements into clinical practice.”
As part of his new role, Dr. Kapoor has been charged with the task of developing a harmonized strategic research plan (SRP) that will set the arthritis research group’s direction for the next five years, while laying the groundwork for its continued success beyond the next five years. In addition, Dr. Kapoor will be working with the Toronto General & Western Hospital Foundation to help align fundraising priorities with the SRP.
In developing the SRP, Dr. Kapoor will begin an open consultation process with Division Heads, Drs. Aileen Davis (Healthcare Outcomes and Research) and James Eubanks (Genetics & Development); other members of the Krembil Research Council; arthritis research group members, who have active research programs in ankylosing spondylitis, osteoarthritis, pain, psoriatic arthritis, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, and other bone, muscle and joint diseases; and clinical leaders.
“The practice of building and implementing a new research plan is an important one,” stresses Dr. Kapoor. “It provides a framework for what we are trying to build, a world leading biomedical research institute, and reinforces why we are building it—to discover cures and improve our patients’ quality of life.”
