Sinai Health

Growing up with a dog may be good for your gut health: Study

rahul.kalvapalle — Thu, 26 Sep 2024 14:44:39 +0000

Growing up with a dog may be good for your gut health: Study

rahul.kalvapalle Thu, 09/26/2024 - 10:44

Cutline

Living with a dog between ages five and 15 is associated with reduced risk of developing Crohn’s disease, according to new research from Sinai Health and U of T (photo by Kseniya Starkova/Getty Images)

Jovana Drinjakovic

Topic

Breaking Research

Department of Immunology

Department of Medicine

Sinai Health

Temerty Faculty of Medicine

Lunenfeld-Tanenbaum Research Institute

Mount Sinai Hospital

Subheadline

Research from Sinai Health and U of T found early exposure to dogs is linked to a healthier gut and reduced risk of developing Crohn's disease

Dog lovers can attest to the range of benefits that come with having a canine companion, but improved gut health likely isn’t one of them.

That may be about to change following research from Sinai Health and the ��߲ݴ�ý that shows exposure to dogs during childhood is linked to beneficial changes in gut bacteria, gut permeability and blood biomarkers.

The study, published in Clinical Gastroenterology and Hepatology, found living with a dog between ages five and 15 is associated with a healthier gut microbiome and reduced risk of developing Crohn’s disease.

The research shines new light on how environmental factors influence the onset of Crohn’s – an inflammatory bowel condition – and could inform future prevention strategies.

For the study, researchers led by Kenneth Croitoru and Williams Turpin of Mount Sinai Hospital’s Centre for Inflammatory Bowel Disease (IBD) investigated how dozens of environmental factors impact the likelihood of developing Crohn’s as part of their overarching effort to be able to predict those at risk and potentially intervene early.

“The idea behind predicting someone's risk of disease is that you can then also begin to understand who you might want to do something to try and prevent disease,” says Croitoru, a clinician-scientist at the Lunenfeld-Tanenbaum Research Institute (LTRI), part of Sinai Health, and a professor of medicine and immunology at U of T’s Temerty Faculty of Medicine.

Croitoru notes the study doesn’t reveal why living with a dog makes someone less prone to Crohn’s disease. “We have established associations between environmental factors and Crohn’s and are now trying to understand how these environmental factors affect the triggering of the disease,” says Croitoru, who is also a gastroenterologist at Mount Sinai Hospital.

The study also found living with a large-sized family in the first year of life to reduce the likelihood of getting Crohn’s. It also found people who lived with a bird at the time of study were more likely to develop the disease.

Caused by inflammation in the gastrointestinal tract, Crohn’s disease can have far-reaching consequences on overall health and well-being. Its incidence among children under 10 has doubled since 1995, while the annual cost of inflammatory bowel disease to Canada is estimated at $5.4 billion per year, according to Crohn’s and Colitis Canada, a national non-profit.

The likelihood of getting Crohn’s is strongly influenced by genetics, but the environment also plays a role, says Croitoru, who holds the Canada Research Chair in Inflammatory Bowel Diseases. While we can’t change our genes, we can modify our surroundings and diet, for example, to potentially prevent the disease from occurring.

These findings come from the Genetic, Environmental and Microbial (GEM) Project, the largest study of its kind that seeks to identify potential triggers of Crohn’s disease.

Coordinated at Mount Sinai Hospital since 2008, the GEM Project has been collecting comprehensive medical and lifestyle data from over 5,000 healthy first-degree relatives of people who have Crohn’s and come from all over the world, including Australia, Canada, Israel, New Zealand, the U.K. and the U.S.

The project is funded by Crohn’s and Colitis Canada, the Canadian Institutes of Health Research and the Helmsley Charitable Foundation.

In the 15 years since the study began, over 120 people have developed the disease. “By understanding what is different about those who develop the disease, we should be able to predict who is at risk,” says Croitoru.

Previously, the group identified differences in the microbiome and other biomarkers in people who go on to develop Crohn’s and those who don’t.

In another recent report published in Gastroenterology, Sun-Ho Lee, a clinician-scientist at Mount Sinai Hospital’s IBD Centre and an assistant professor at the Institute of Medical Science at Temerty Medicine, used available data and machine learning to develop an “integrative risk score” that predicts the risk of Crohn’s with a high degree of accuracy.

But risk prediction is only the first step, says Croitoru, whose ultimate goal is to be able to intervene and prevent the disease from starting.

He and his team are now conducting research that seeks to devise and test strategies for prevention by, for example, adding supplements to the diet to promote a healthy microbiome.

“Sinai Health is committed to groundbreaking research and bringing those discoveries to patients," said Anne-Claude Gingras, director of LTRI and vice-president of research at Sinai Health.

“By integrating genetic, environmental, and microbial data, Dr. Croitoru and colleagues are paving the way towards personalized intervention strategies that could significantly reduce the incidence of Crohn’s disease.”

New study identifies two critical genes in pancreatic tumours

rahul.kalvapalle — Thu, 25 Jul 2024 14:46:33 +0000

New study identifies two critical genes in pancreatic tumours

rahul.kalvapalle Thu, 07/25/2024 - 10:46

Cutline

A team led by Daniel Schramek, a researcher at the Lunenfeld-Tanenbaum Research Institute (LTRI), Sinai Health and U of T's Temerty Faculty of Medicine, identified two genes that are associated with fast-growing tumours in the pancreas (photo courtesy of Mount Sinai)

Jovana Drinjakovic

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Lunenfeld-Tanenbaum Research Institute

Cancer

Molecular Genetics

Research & Innovation

Subheadline

The findings mark a significant step forward in research on pancreatic cancer, a disease that has seen little progress in treatment options

��߲ݴ�ý researchers have identified two genes that play a critical role in tumour growth in the pancreas – findings that have significant implications for understanding and treating pancreatic cancer.

The tumour suppressor genes USP15 and SCAF1 were discovered by a research team led by Daniel Schramek, a senior investigator at the Lunenfeld-Tanenbaum Research Institute (LTRI) and deputy director of discovery research and Tony Pawson Chair in Cancer Research at Sinai Health.

The team found that people who have mutations in these genes are more likely to develop fast-growing tumours – but these tumours are also more susceptible to chemotherapy. The findings, described in a study published in Nature Communications, mark a significant step forward in research on pancreatic cancer, a disease that has seen little progress in treatment options.

“While mutations in USP15 and SCAF1 make tumours more aggressive, they also sensitize tumours towards standard chemotherapy,” says Schramek, who is also an associate professor in the department of molecular genetics and Canada Research Chair in functional cancer genomics at the Temerty Faculty of Medicine.

“And that means that you could stratify patients and they should have a better response to treatment.”

The project was spearheaded by Sebastien Martinez, a former postdoctoral fellow at LTRI who is now a senior scientist at Centre de Recherche en Cancérologie de Lyon (CRCL) in France.

Pancreatic cancer continues to have few treatment options with devastatingly low survival rates, under five years post-diagnosis. According to one estimate, pancreatic cancer could be the second leading cause of cancer deaths in the United States by 2040.

Schramek's team achieved their breakthrough by leveraging advances in genomic medicine, specifically tumour DNA sequencing, to identify mutations and genome editing technologies.

“Sequencing tumours allows you to find the genes that are affected and use that knowledge to develop treatments. But the problem is that every cancer has a plethora of mutations, and not all of them are disease-causing,” says Schramek.

Cancers often feature common mutated genes in many patients, along with hundreds of less frequent mutations that appear in a smaller subset. While mutations in USP15 and SCAF1 were found in less than five per cent of patients, their effects on cancer remained unclear.

Traditionally, tumour suppressor genes have been pinpointed by sequentially deleting genes in cancer cell lines and noting which deletions increase cell growth. However, these cell-based studies don't replicate the tumour's natural environment and interactions with the immune system, which are crucial for cancer progression. This likely explains why previous screens overlooked USP15 and SCAF1.

A few years ago, Schramek's team developed a genome editing approach enabling them to remove hundreds of genes simultaneously from individual cells. This method helps identify genes that, when absent, trigger cancer in the natural body environment.

Utilizing this technology, the Schramek lab targeted 125 genes recurrently mutated in patient pancreatic tumours and pinpointed USP15 and SCAF1 as crucial tumor suppressors and potentially prognostic factors for chemotherapy response.

It just so happens that these genes are also absent in about 30 per cent of patients due to common genomic rearrangements in cancer.

This finding indicates that as many as a third of pancreatic patients who lack these genes might benefit from chemotherapy and have better outcomes.

“Historically, mutations in USP15 and SCAF1 would have been considered less important because they are not found in many patients,” Schramek says. “Our work shows that it is critical that we understand the functional consequences of these rare mutations as they can reveal new biology and therapeutic opportunities”

Anne-Claude Gingras, director of the Lunenfeld-Tanenbaum Research Institute and vice-president of research at Sinai Health, says the study “represents an important step forward in our understanding of the genes involved in pancreatic cancer.

“It also shows how a cutting-edge technology developed at Sinai Health is enabling new discoveries with the potential to create benefits to patients.”

This research was supported by funding from the Ontario Institute of Cancer Research, Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Foundation, Terry Fox Research Institute, Canadian Cancer Society Research Institute, Pancreatic Cancer Canada and the Canadian Institute of Health.

Study points to improved detection of thyroid cancer

Christopher.Sorensen — Thu, 04 Jul 2024 20:22:19 +0000

Study points to improved detection of thyroid cancer

Christopher.Sorensen Thu, 07/04/2024 - 16:22

Cutline

(photo by Basak Gurbuz Derman/Getty Images)

Gabrielle Giroday

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Cancer

Research & Innovation

Subheadline

“(This finding) enhances the preoperative diagnostic accuracy for patients in order to avoid unnecessary surgery for benign thyroid nodules”

Researchers from Sinai Health and the ��߲ݴ�ý have gleaned new insights into how thyroid cancer could be more effectively treated.

The study, which looked at thyroid tumour tissues and thyroid nodule biopsies from 620 patients at Mount Sinai Hospital from 2016 to 2022, examined whether differences in patients' RAS genomic variants were reflected in the status of their tumours. It also investigated the presence of the variant BRAF V600E and TERT promoter variants in the patient’s samples.

Researchers ultimately concluded that differences in RAS in combination with BRAF V600E and TERT promoter variants could be used to arrive at more accurate cancer diagnoses in patients with indeterminate thyroid nodules.

“The findings help promote understanding of the interpatient differences in genomic variation among patients who carry the same genetic mutation, thereby facilitating individualized treatment based on the extent of the mutation present in the patient,” says Guodong (David) Fu, a researcher at the Lunenfeld-Tanenbaum Research Institute and the Alex and Simona Shnaider Research Laboratory in Molecular Oncology at Mount Sinai Hospital.

Fu adds that researchers developed novel molecular assays for the study using digital polymerase chain reaction, a technique that means they could sensitively quantify the genetic mutation level of the patient materials.

The results were published recently in JAMA Network. Other researchers involved in the study included: Ronald Chazen, also of the Lunenfeld-Tanenbaum Research Institute and the Alex and Simona Shnaider Research Laboratory in Molecular Oncology, and Christina MacMillan, a pathologist at Sinai Health and an assistant professor in the Temerty Faculty of Medicine’s department of laboratory medicine and pathobiology, and Ian Witterick, surgeon-in-chief at Sinai Health and a professor in Temerty Medicine’s department of otolaryngology – head and neck surgery.

The paper notes that there has been a sharp increase in papillary thyroid cancer since the 1980s, and that in 30 per cent of cases where a fine-needle aspiration biopsy of a suspected nodule takes place, there is an indeterminate diagnosis that may lead to a diagnostic surgery.

Fu says research that assists with precision thyroid cancer detection is important for many reasons, including that some patients who seek treatment for thyroid tumours end up finding out their tumours are benign after diagnostic surgery. The findings could help medical practitioners differentiate low-risk tumours from high-risk ones, he says, and help avoid unneeded surgical procedures.

“(This finding) enhances the preoperative diagnostic accuracy for patients, in order to avoid unnecessary surgery for benign thyroid nodules,” says Fu.

Witterick, who is also otolaryngologist-in-chief at Mount Sinai Hospital, says the research is important because identifying differences in genomic variants between patients can enhance precision in cancer detection, especially diagnosing malignancies before surgery and distinguishing low-risk cancers from more aggressive ones.

A master neuron controls movement in worms, with implications for human disease: Study

Christopher.Sorensen — Thu, 16 May 2024 15:01:59 +0000

A master neuron controls movement in worms, with implications for human disease: Study

Christopher.Sorensen Thu, 05/16/2024 - 11:01

Cutline

Researchers at the Lunenfeld-Tanenbaum Research Institute have revealed the crucial role of a neuron called AVA in controlling the worm C. elegans’s ability to shift between forward and backward motion ( photo by ZEISS Microscopy from Germany)

Jovana Drinjakovic

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Cell and Systems Biology

Faculty of Arts & Science

Molecular Genetics

Research & Innovation

Subheadline

The discovery offers a major new insight into a neural circuit that scientists have studied since the inception of modern genetics.

Researchers at Sinai Health and the ��߲ݴ�ý have uncovered a mechanism in the nervous system of the tiny roundworm C. elegans that could have significant implications for treating human diseases and advancing robotics.

The study, led by Mei Zhen and colleagues at the Lunenfeld-Tanenbaum Research Institute, was published in the journal Science Advances and reveals the crucial role of a specific neuron called AVA in controlling the worm’s ability to shift between forward and backward motion.

Crawling towards food sources and swiftly reversing from danger is a matter of life and death for the worms. This type of behaviour, where two actions are mutually exclusive, is common in many animals including humans – we cannot sit and run at the same time, for example.

Scientists long believed that control of movements in worms was due to straightforward reciprocal actions between two neurons: AVA and AVB. The former was thought to promote backward motion while AVB facilitated forward motion, with each neuron inhibiting the other to control movement direction.

However, the new data from Zhen’s team challenge this notion, uncovering a more complex interaction where the AVA neuron plays a dual role. It not only instantly stops forward motion by inhibiting AVB, but also maintains a longer-term stimulation of AVB to ensure a smooth transition back to forward movement.

The discovery highlights the AVA neuron’s ability to finely control movement through distinct mechanisms, depending on different signals and across different time scales.

“In terms of engineering, this is a very economical design,” said Zhen, who is also a professor of molecular genetics in U of T’s Temerty Faculty of Medicine. “The strong, robust inhibition of the backward circuit allows the animals to respond to bad environments and escape. At the same time, the controller neuron continues to put in constitutive gas into the forward circuit to generate movement towards safer places.”

Jun Meng, a former PhD student in the Zhen lab who led the research, said understanding how animals transition between such opposing motor states is crucial for insights into how animals move as well as neurological disorder research – and that the worms provide a unique window into basic neural wiring that's to their simple, see-through bodies.

The discovery that the AVA neuron plays such a dominant role offers a major new insight into the neural circuit that scientists have studied since the inception of modern genetics over half a century ago. The Zhen lab successfully leveraged cutting-edge technology to precisely modulate the activity of individual neurons and record data from living worms in motion.

Zhen, who is also a professor of cell and systems biology at U of T’s Faculty of Arts & Science, emphasizes the importance of interdisciplinary collaboration in this research. Meng performed key experiments, while neuronal electrical recordings were conducted by Bin Yu, a PhD student in Shangbang Gao’s lab at Huazhong University of Science and Technology in China.

Tosif Ahamed, a former post-doctoral researcher in the Zhen lab and now a Theory Fellow at the HHMI Janelia Research Campus in the United States, led mathematical modelling efforts that were crucial for testing hypotheses and gaining the new insights.

The findings provide a simplified model to study how neurons can manage multiple roles in movement control – a concept that might extend to human neurological conditions.

For example, AVA’s dual role depends on its electric potential, which is regulated by ion channels on its surface. Zhen is already exploring how similar mechanisms could be involved in a rare condition known as CLIFAHDD syndrome, caused by mutations in similar ion channels. Additionally, the new findings could inform the development of more adaptable and efficient robotic systems capable of complex movements.

“From the origin of modern science to the forefront of today’s research, model organisms like C. elegans have been instrumental in peeling back the layers of complexity in our biological systems," said Anne-Claude Gingras, director of the Lunenfeld-Tanenbaum Research Institute, vice-president of research at Sinai Health and a professor of molecular genetics in U of T’s Temerity Faculty of Medicine.

“This research is a great example of how much we can learn from simple animals, to then think about applying this new knowledge to advancing medicine and technology.”

The research was supported by the Canadian Institute of Health Research, the Natural Sciences and Engineering Research Council of Canada, the National Natural Science Foundation of China and the European Research Council.

Canadian Hub for Health Intelligence and Innovation in Infectious Diseases awarded $72 million

Christopher.Sorensen — Mon, 06 May 2024 16:07:51 +0000

Canadian Hub for Health Intelligence and Innovation in Infectious Diseases awarded $72 million

Christopher.Sorensen Mon, 05/06/2024 - 12:07

Cutline

(photo by Nick Iwanyshyn)

Topic

Institutional Strategic Initiatives

Leah Cowen

PRiME

Sinai Health

Temerty Faculty of Medicine

Unity Health

Chemistry

Faculty of Applied Science & Engineering

Faculty of Arts & Science

Research & Innovation

Subheadline

Federal funding will be used to strengthen talent development and health intelligence in order to respond to emerging health threats

Four research programs in the Canadian Hub for Health Intelligence and Innovation in Infectious Diseases (HI³) have received $72 million in federal funding from the Canada Biomedical Research Fund (CBRF) and Biomedical Research Infrastructure Fund (BRIF), bolstering the country’s biomanufacturing capacity and readiness to respond to emerging health threats.

Support for HI³ and the four funded research programs through the CBRF and BRIF is part of a larger investment in Canada’s Biomanufacturing and Life Sciences Strategy. The strategy aims to grow a strong, competitive domestic life sciences sector with cutting-edge biomanufacturing capabilities and to improve the country’s ability to respond to future health challenges.

HI³ – a coalition of 87 academic, hospital, research networks, industry, government, not-for-profit and community partners – was one of five national hubs established in March 2023 with CBRF funding.

Together, the four awarded programs will provide critical health intelligence data to guide the co-development of health threat surveillance platforms and next-generation precision interventions by the hub’s academic and industry partners, while building a highly skilled workforce to support Canada’s growing biomanufacturing and life sciences sector.

“Congratulations to HI³ and the collaborative teams behind these CBRF-funded programs. These four programs leverage the tremendous expertise of the ��߲ݴ�ý's researchers and our partners in academia, hospitals, industry and other sectors to develop the talent, tools and data required to be at the forefront of emerging health threats,” said Leah Cowen, U of T’s vice-president, research and innovation, and strategic initiatives.

“On behalf of the ��߲ݴ�ý and HI³, I thank the government of Canada for its investment in building a strong domestic life sciences sector ready to take on the health challenges of today and tomorrow.”

One of the CBRF-funded programs is the Biomanufacturing Hub Network (BioHubNet), an immersive talent development program based at U of T and led by University Professor Molly Shoichet along with Darius Rackus, an assistant professor of chemistry and biology at Toronto Metropolitan University, and Gilbert Walker, a professor of chemistry at U of T.

“With world-leading scientists and researchers established across Canadian leading research institutions, Canada is home to a competitive and robust biomanufacturing and life sciences sector. We made a promise to Canadians that we would rebuild the domestic sector,” said François-Philippe Champagne, Canada’s minister of innovation, science and industry. “With this investment, our government is delivering on this promise by supporting the excellent innovations, collaborations and infrastructures necessary to rapidly respond to future public health threats and keep Canadians safe.”

The predicted supply of biomanufacturing workers is only enough to fill one-quarter of the positions that will be needed in the sector by 2029, according to a 2021 report from BioTalent Canada.

To address the shortage, BioHubNet will leverage its 26 industry and training partners – which include multinational and homegrown biotechnology companies, as well as five Ontario colleges and nearly $19 million in funding from CBRF – to develop a range of training programs and curricula that provide experiential, hands-on learning to graduate students, postdoctoral fellows and others who are ready to transition to industry.

The program will also outfit entrepreneurs with the skills and resources they need to commercialize their lab-based innovations, further strengthening the translational pipeline. Over the next four years, BioHubNet will produce close to 1,000 highly skilled workers through micro-credential courses, industry internships, academic exchange placements and entrepreneurial training.

A central tenet underlying all BioHubNet’s offerings is a commitment to create more equitable and inclusive participation in the biomanufacturing and life sciences sectors through intentional recruitment and active support for trainees from under-represented groups.

“Canada’s future as a leader in bio-innovation depends on having highly qualified workers, yet the sector is predicted to face severe workforce shortages in the coming years,” says Shoichet, who is the Michael E Charles Professor in Chemical Engineering at U of T and scientific director of PRiME Next-Generation Precision Medicine, a U of T institutional strategic initiative based at the Leslie Dan Faculty of Pharmacy.

“By expanding the pipeline of skilled research talent in Canada, BioHubNet will accelerate the translation of promising discoveries from bench to market and ensure that this country’s biomanufacturing sector continues to grow and attract further international investment.”

In addition to BioHubNet, three other research programs were also funded:

The Integrated Network for the Surveillance of Pathogens: Increasing Resilience and capacity in Canada’s pandemic response (INSPIRE) based at the University of Windsor. Co-led by Windsor professor Mike McKay and University of Guelph professor Lawrence Goodridge, the INSPIRE program leverages community-level wastewater surveillance data, infrastructure and expertise to monitor the arrival and spread of infectious threats. The program also received infrastructure funding from BRIF to implement technologies and processes across its network that will streamline wastewater surveillance efforts to be more rapid, agile and sensitive. Importantly, these infrastructure supports will expand wastewater monitoring capacity in northern Ontario and at the Windsor-Detroit border to strengthen supply chains.
The Prepare, React, Collect, Innovate, Share and Engage (PRECISE) Diagnostic Platform, based at Sinai Health and co-led by Jennie Johnstone and Anne-Claude Gingras – who are both faculty members in U of T’s Faculty of Medicine – will advance a comprehensive, streamlined approach for responding to emerging threats by driving the timely development of rapid diagnostic tools that will scale up testing capacity and reduce reliance on global supply chains.
The Pandemic Preparedness Engaging Primary Care and Emergency Departments (PREPARED) program, based at Unity Health Toronto and led by Andrew Pinto, who is a faculty member in the Temerty Faculty of Medicine, aims to engage primary care clinics and emergency departments across the country to enhance disease monitoring, improve patient care and health system efficiency, accelerate the development of medical countermeasures and boost recruitment to clinical trials.

All four research programs reflect the hub’s extensive network of nearly 100 partners from academia, hospital, industry, public and other sectors. The programs leverage the collective resources and expertise of this network, including U of T’s position as a global leader in artificial intelligence, data, life sciences and engineering, and the Toronto Academic Health Sciences Network’s strong track record of clinical impact and health-care innovation.

“Our goal at HI³ is to advance mission-driven, team-based science that will help Canada be more prepared, resilient and independent in the face of emerging health threats,” said Jen Gommerman, co-director of HI³ and a professor of immunology in U of T’s Temerty Faculty of Medicine.

“As we support and grow these four research programs, we will continue to work closely with our hub partners and with our counterparts across the country to ensure that we have the capacity and resources needed to respond in a co-ordinated, effective and equitable manner.”

Researchers devise new method to find proteins for targeted treatment of disease

Christopher.Sorensen — Tue, 26 Mar 2024 18:12:33 +0000

Researchers devise new method to find proteins for targeted treatment of disease

Christopher.Sorensen Tue, 03/26/2024 - 14:12

Cutline

Visiting Scientist Juline Poirson and Associate Professor Mikko Taipale worked with researchers at Sinai Health to develop a method to interrogate the entire human proteome for “effector” proteins, which can influence the stability of other proteins (supplied images)

Anika Hazra

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Donnelly Centre for Cellular & Biomolecular Research

Research & Innovation

Subheadline

“Targeting proteins through induced proximity is a new and promising area of biomedical research”

Researchers at Sinai Health and the ��߲ݴ�ý have created a new platform to identify proteins that can be used to control the stability of other proteins – a new and largely unrealized approach to treating diseases.

The researchers developed a method to interrogate the entire human proteome for “effector” proteins, which can influence the stability of other proteins via induced proximity. The approach effectively attempts to hijack cellular processes for therapeutic purposes.

The study marks the first time researchers have searched for effector proteins on this scale, and has identified many new effectors that could potentially be used to develop new drugs.

“We found more than 600 new effector proteins in 14,000 genes,” said Juline Poirson, first author on the study and visiting scientist at U of T’s Donnelly Centre for Cellular and Biomolecular Research. “Over 200 of the new effectors can efficiently degrade their target proteins, while about 400 effectors were capable of stabilizing, and thereby increasing the abundance of, an artificial target protein.”

The study, which involved researchers at Sinai Health’s Lunenfeld-Tanenbaum Research Institute, was published in the journal Nature.

“Targeting proteins through induced proximity is a new and promising area of biomedical research,” said Mikko Taipale, principal investigator on the study and an associate professor of molecular genetics at the Donnelly Centre and in the Temerty Faculty of Medicine. “Not only did we find new effectors worth further investigation for drug discovery, we developed a synthetic platform that can be used to conduct unbiased, proteome-wide, induced-proximity screens to continue expanding the library of effector proteins.”

The effectors currently in use for targeted protein degradation and stabilization are E3 ubiquitin ligases (E3s) and deubiquitinases (DUBs), respectively. E3 is an enzyme that transfers the ubiquitin molecule to the target protein, which essentially flags the protein for a proteosome to digest it. On the other hand, a DUB enzyme removes the ubiquitin tag from a protein, thereby preventing the protein from being recognized and degraded by a proteosome.

The results of the study demonstrate that E3s are quite varied in the degree to which they can degrade target proteins. The research team also discovered four of what they call “angry E3s,” which consistently degrade targets regardless of other factors, such as the location of the target within the cell.

One surprising finding was that some of the strongest effectors for targeted protein degradation were E2 conjugating enzymes, instead of E3s. These differ from E3s in that they are involved at an earlier step of protein degradation and do not directly engage the target protein. Because E2s were not considered to be easily targeted with drugs, they had not been harnessed for protein degradation until recently. They represent, however, the untapped potential of stronger effectors than ones currently in use.

The study demonstrates that exploring the whole proteome for induced proximity offers enormous opportunities for therapeutic interventions.

KLHL40, one of the identified effectors, could potentially be hijacked for targeted protein stabilization to treat skeletal muscle disorders. The research team also found that targeted protein degradation with FBXL12 and FBXL15 effectors could be particularly useful in treating chronic myeloid leukemia.

Targeted protein degradation and stabilization are innovative methods of drug discovery that have thus far been plagued with the “protein pair problem,” where the best effector for a target protein cannot be predicted accurately. Matching a target protein with the right effector is essential to successfully and safely facilitate degradation and stabilization processes in tissues.

“The synthetic screening platform developed by our team solves the protein matching issue through rapid, large-scale testing of effector and target protein interactions,” said Poirson. “We’re confident that an unbiased induced-proximity approach can be used to find effectors for almost any target.”

The research was supported by the David Dime and Elisa Nuyten Catalyst Fund, the Mark Foundation for Cancer Research, the Charles H. Best Postdoctoral Fellowship and the Canadian Institutes of Health Research (CIHR) Fellowship.

U of T receives $10 million from Ontario government for modernization of high containment facility

Christopher.Sorensen — Mon, 18 Mar 2024 18:15:01 +0000

U of T receives $10 million from Ontario government for modernization of high containment facility

Christopher.Sorensen Mon, 03/18/2024 - 14:15

Cutline

(photo by Julia Soudat)

Betty Zou

Topic

Our Community

Emerging and Pandemic Infections Consortium

Institutional Strategic Initiatives

Sinai Health

Sunnybrook Health Sciences Centre

Temerty Faculty of Medicine

Unity Health

Health

Hospital for Sick Children

Research & Innovation

University Health Network

Subheadline

Renewal of the 20-year-old facility, which allows researchers to study high-risk pathogens, will provide increased capacity to develop new vaccines and therapeutics

Canada’s ability to respond rapidly to emerging infectious diseases is taking a step forward with a $9.9-million investment from the Ontario government to support critical research infrastructure updates to the Toronto High Containment Facility (THCF), which houses the largest containment level 3 lab in the province.

The facility, located at the ��߲ݴ�ý, is specially equipped to allow researchers to study high-risk pathogens, such as SARS-CoV-2, HIV, tuberculosis and mpox, in a safe and secure way.

Research undertaken at the current facility has advanced our understanding of infectious diseases and strengthened our ability to respond to emerging health threats.

“The THCF strengthens Ontario’s position as a prime location for globally leading companies and top talent to discover and commercialize cutting-edge technologies, while improving our preparedness for future health challenges,” says Leah Cowen, U of T’s vice-president, research and innovation, and strategic initiatives. “The updated facility will enhance Canada’s health infrastructure and health security, and ensure that Canadian researchers are trained and ready to respond to emerging infectious diseases.”

The provincial funding builds on a previous $35-million investment from the Canada Foundation for Innovation to support efforts to revitalize and expand the THCF and to transform it into the largest academic high-containment research centre in Canada.

The renewal of the 20-year-old facility will provide increased capacity to use state-of-the-art approaches supporting academic research projects as well as collaborative industry-led efforts to develop new vaccines and therapeutics for Canadians. The new provincial investment will also allow the facility to meet the growing demand from industry and public sector partners while maintaining ongoing research projects and an agile responsiveness to future outbreaks.

“The new THCF will allow our researchers to work on the most urgent infectious disease threats, provide greater opportunities to engage with government agencies and industry partners, and allow us to provide unique training opportunities for the next generation of infectious disease leaders, building a strong foundation for Canada’s response to future outbreaks,” says Scott Gray-Owen, academic director of the THCF and a professor of molecular genetics in U of T’s Temerty Faculty of Medicine.

The provincial support is part of a suite of investments through the Ontario Research Fund and the Early Researcher Awards that also include support for quantum and artificial intelligence projects at U of T. Support has also been extended to advance an infrastructure renewal of the province’s Advanced Research Computing (ARC) systems, including U of T’s Niagara ARC supercomputer, used by researchers across the country.

As the only high containment facility of its kind in the Greater Toronto Area, the THCF is a unique asset to the life sciences ecosystem in the region, which is home to 55 per cent of Canada’s pharmaceutical companies. The modernized facility will be able to support greater engagement with industry partners to advance made-in-Ontario therapeutics such as the experimental drug paridiprubart from Markham-based Edesa Biotech, which is currently being tested in a Phase 3 clinical trial to treat acute respiratory distress syndrome, a common complication from COVID-19 or influenza infections.

In addition to industry partners, the THCF has been used by federal and provincial agencies including the Public Health Agency of Canada, Bank of Canada, Rogers Hixon Ontario Human Milk Bank and Ontario Ministry of Natural Resources and Forestry.

The THCF renewal will also be undertaken in collaboration with U of T’s hospital partners: The Hospital for Sick Children, Sinai Health, Sunnybrook Health Sciences Centre, Unity Health Toronto and University Health Network. Construction of the facility has begun but the university is seeking additional funding to complete the project.

Based at the Temerty Faculty of Medicine, the THCF is the cornerstone of the Emerging and Pandemic Infections Consortium, a U of T institutional strategic initiative that brings together the university and Toronto Academic Health Science Network (TAHSN) hospital partners to drive innovative approaches to infectious diseases and prepare for future pandemics. It is also a key infrastructure resource for the Canadian Hub for Health Intelligence and Innovation in Infectious Diseases (HI3) which was established through the Canada Biomedical Research Fund. The hub brings together over 90 partners across several sectors to bolster Canada’s biomanufacturing capacity to ensure a fast and co-ordinated response to future pandemics and infectious threats.

The revitalized THCF will also have the capacity to train more than 100 new highly qualified professionals over a five-year period with industry-relevant skills, including manufacturing practices and vaccine and therapeutics development.

At the beginning of the COVID-19 pandemic, the THCF was the first lab in Canada – and one of the first in the world – to isolate the new coronavirus in March 2020. The facility and its highly trained staff played a key role in accelerating research breakthroughs that guided the pandemic response including, for example, methods to allow safe reuse of personal protective equipment in health-care settings and to ensure safe human milk banking for premature infants.

The THCF was also a core element of EPIC’s mpox rapid research response, housing a biobank of samples from patients with mpox which are being used by researchers to better understand the dynamics of viral shedding and other important questions about the disease.

In addition to a larger physical space, the updated facility will include a state-of-the-art high containment insectary to enable research on mosquito-borne viruses like Chikungunya, dengue, Zika and yellow fever. With its modular design and enhanced safety features, the new facility will also be better positioned to respond to emerging pathogens like highly pathogenic avian influenza.

Celebrating U of T's impact on hockey in Toronto

Christopher.Sorensen — Thu, 01 Feb 2024 14:05:36 +0000

Celebrating U of T's impact on hockey in Toronto Christopher.Sorensen Thu, 02/01/2024 - 09:05

Topic

Our Community

Sinai Health

Alumni

Faculty of Arts & Science

Faculty of Kinesiology & Physical Education

Hockey

Rotman Commerce

Varsity Blues

Toronto is a sports city – and hockey is close to its heart.

In a new video, members of the ��߲ݴ�ý community reflect on how U of T’s Varsity Blues hockey program inspired the Toronto Maple Leafs – and how the future of hockey is diverse and inclusive.

“I’m excited about the future of hockey because I think we’ve never been in a better place – especially with the creation of a professional women’s league,” says Jayna Hefford, a five-time Olympic medallist in women’s hockey who is now senior vice-president of the Professional Women’s Hockey League and a former Varsity Blues Player.

“If we want Canada and hockey to thrive, we need as many people playing as we can.”

Cole Purboo, a fourth-year student at Rotman Commerce and captain of the Varsity Blues men’s hockey team, says he, too, believes the future of the game is one that is “more diverse and more accessible for more people.”

The video also explores how the Tanenbaum Institute for Science in Sport at U of T and Sinai Health is shaping the future of athletics and ensuring that sports are for everyone.

“We saw an opportunity to encourage engagement, drive performance and accelerate recovery through groundbreaking and globally recognized research,” says Larry Tanenbaum, philanthropist and chair of Maple Leaf Sports & Entertainment, “allowing athletes of all levels and ability to reach their maximum potential.”

Interviews in this video include:

Larry Tanenbaum, chair of Maple Leaf Sports & Entertainment, philanthropist behind the U of T Tanenbaum Institute for Science in Sport at U of T and Sinai Health
Bruce Kidd, professor emeritus, sport and public policy, Faculty of Kinesiology & Physical Education
Cole Purboo, fourth-year student at Rotman Commerce, Varsity Blues men’s hockey team Captain
Jayna Hefford, senior vice-president hockey operations for the Professional Women’s Hockey League, Varsity Blues Women’s Hockey 1996-97

Breast milk may have protective effects against COVID-19: Researchers

Christopher.Sorensen — Mon, 29 Jan 2024 18:38:03 +0000

Breast milk may have protective effects against COVID-19: Researchers

Christopher.Sorensen Mon, 01/29/2024 - 13:38

Cutline

Samantha Ismail led a study by researchers at U of T and its partner hospitals that looked for SARS-CoV-2 antibodies in human breast milk (supplied image)

Betty Zou

Topic

Breaking Research

COVID-19

Emerging and Pandemic Infections Consortium

Institutional Strategic Initiatives

Sinai Health

Sunnybrook Health Sciences

Temerty Faculty of Medicine

Laboratory Medicine and Pathobiology

Research & Innovation

Vaccines

Subheadline

“COVID-19 vaccination and infection result in antibodies in human milk that have neutralizing capacity"

The COVID-19 pandemic was an especially harrowing time for pregnant people and new parents.

The uncertainties about how the new coronavirus could affect a pregnant person and their developing fetus – not to mention being cut off from support networks – left many expecting parents feeling isolated and anxious.

“It was a very surreal time,” says Jenny Doyle, a Toronto mom who gave birth to her first child, Elliott, in 2020 and spent hours researching how the first vaccines made available the following year might affect her and her child. “At the time, vaccines for infants were still so far away. I remember hoping that some of the protection I’d received from my vaccine would pass through to Elliott.”

Now, new findings from a study led by researchers at the ��߲ݴ�ý and its partner hospitals suggest that is the case.

Published in the American Journal of Clinical Nutrition, the study looked for antibodies against SARS-CoV-2 in breast milk from three different cohorts: individuals who contracted COVID-19 while pregnant or nursing, routine milk bank donors and individuals who received two doses of the COVID-19 vaccine while pregnant or nursing.

The researchers detected antibodies in breast milk from roughly half of the people in the COVID-19 positive cohort. That’s compared to less than 5 per cent of routine milk bank donors, who did not have any known exposures to COVID-19. In the vaccinated cohort, they found that antibodies levels were higher in people who had received the Moderna vaccine compared to those who had received the Pfizer-BioNTech vaccine. Unexpectedly, people who had shorter intervals between their first and second doses had higher antibody levels than those who waited longer between their immunizations.

“That finding definitely surprised me,” says Samantha Ismail, the study’s first author who completed her master’s degree in the lab of Deborah O’Connor, the Earle W. McHenry Professor and chair of Temerty Medicine’s department of nutritional sciences. “In [blood] serum, it’s the other way around where longer intervals between doses typically result in higher antibody levels, suggesting that something different is happening in this lactating population.”

In addition to Ismail and O’Connor, the study was led by Sharon Unger, medical director of the Roger Hixon Ontario Human Milk Bank at Sinai Health and a U of T professor of medicine and nutritional sciences, and Susan Poutanen, microbiologist and infectious disease consultant and Sinai Health and U of T associate professor of laboratory medicine and pathobiology.

The team took the study one step further by showing that some breast milk samples could prevent SARS-CoV-2 from infecting cells in a lab setting. Within the COVID-19 positive cohort, milk that contained antibodies against the virus were more likely to be neutralizing and immunization with the Moderna vaccine was associated with a stronger neutralizing capacity than the Pfizer-BioNTech vaccine.

The researchers also found a small but significant number of breast milk samples that prevented SARS-CoV-2 infection despite having undetectable levels of antibodies, suggesting that there could be other components in human milk that are active against SARS-CoV-2.

While these findings provide strong evidence to support the potential protective effects of human milk, Ismail cautions that the study alone is not enough to prove that breast milk provides tangible protection against COVID-19.

“COVID-19 vaccination and infection result in antibodies in human milk that have neutralizing capacity, but we don’t know for sure how the neutralizing capacity seen in the lab translates to protection in infants,” says Ismail, who is now a second-year medical student at U of T.

She points out that previous studies have shown a clear protective effect of antibodies in human milk against other viruses like enterovirus and rotavirus. To date, such studies have not been done with COVID-19.

Even so, the findings provide reassuring news to parents like Doyle, who breastfed her son longer than she had intended to ensure that he was still getting breast milk when she received her second COVID-19 vaccine.

“Trying to figure out how to protect this tiny being in that scary and bleak time, I was grasping at every little piece of information and whatever little piece of hope we had.”

The study was supported by the Canadian Institutes for Health Research and was a collaboration between the department of microbiology at Sinai Health System/University Health Network, the Roger Hixon Ontario Human Milk Bank at Sinai Health System and the Toronto High Containment Facility, where the live SARS-CoV-2 neutralization studies were completed.

It involved contributions from several members of the Emerging and Pandemic Infections Consortium, a U of T institutional strategic initiative. In addition to O’Connor, Poutanen and Unger, they include Scott Gray-Owen, of Temerty Medicine’s department of molecular genetics, Samira Mubareka, of Sunnybrook Health Sciences Centre and Temerty Medicine’s department of laboratory medicine and pathobiology, and Jennie Johnstone and Allison McGeer – both of Sinai Health and Temerty Medicine’s department of laboratory medicine and pathobiology.

Post-meal insulin surge not necessarily a bad thing: Study

Christopher.Sorensen — Fri, 12 Jan 2024 20:24:44 +0000

Post-meal insulin surge not necessarily a bad thing: Study

Christopher.Sorensen Fri, 01/12/2024 - 15:24

Cutline

(photo by Violeta Stoimenova/Getty Images)

Jovana Drinjakovic

Topic

Breaking Research

Sinai Health

Temerty Faculty of Medicine

Banting & Best

Diabetes

Subheadline

Researchers explored the cardiometabolic implications of insulin response over the long term in a way that accounts for baseline blood sugar levels

Researchers at Sinai Health and the ��߲ݴ�ý have unearthed new information about the relationship between insulin levels after eating and long-term heart and metabolic health – research that upends the notion that insulin surge following food intake is a bad thing.

On the contrary, the researchers said, it could be an indicator of good health to come.

Led by Ravi Retnakaran, clinician-scientist at the Lunenfeld-Tanenbaum Research Institute (LTRI), part of Sinai Health, the study – which was published in the Lancet group’s online journal eClinicalMedicine – set out to explore how insulin levels after meals impact cardiometabolic health. While past research has yielded conflicting results, suggesting both harmful and beneficial effects, this new study aimed to provide a clearer picture over an extended period of time.

“The suggestion has been made by some people that those insulin peaks have deleterious effects by promoting weight gain,” said Retnakaran, who is a professor in the department of medicine, the Institute of Medical Science and the Banting & Best Diabetes Centre in U of T’s Temerty Faculty of Medicine. “Sometimes I see patients in the clinic who have adopted this notion – maybe from the internet or what they're reading – that they can't have their insulin level go too high.

“[But] the science is just not conclusive enough to support this notion. Most studies on this topic were either conducted over a short period of time or were based on insulin measurements in isolation that are inadequate and can be misleading.”

While it’s normal for insulin levels to rise after eating to help manage blood sugar, the concern is whether a rapid increase in insulin after a meal could spell bad health. Some believe an insulin surge, especially after eating carbohydrates, promotes weight gain and contributes to insulin resistance, which occurs when the body's cells don't respond well to insulin, making it harder to control blood sugar levels and increasing the risk of type 2 diabetes.

Retnakaran’s team looked at cardiometabolic implications of insulin response over the long term in a way that accounts for baseline blood sugar levels. That’s key because each person has an individual insulin response that varies depending on how much sugar is in the blood.

The study followed new mothers because the insulin resistance that occurs during pregnancy makes it possible to determine their future risk of type 2 diabetes. Over 300 participants were recruited during pregnancy, between 2003 and 2014, and underwent comprehensive cardiometabolic testing – including glucose challenge tests at one, three and five years after giving birth. The glucose challenge test measures glucose and insulin levels at varying times after a person has had a sugary drink containing 75 grams of glucose and following a period of fasting.

While the test is commonly used by health professionals, it can be misleading if one does not account for baseline blood sugar.

“It’s not just about insulin levels; it’s about understanding them in relation to glucose,” Retnakaran said, pointing out that this is where many past interpretations fell short. A better measurement, he said, is the corrected insulin response (CIR) that accounts for baseline blood glucose levels, and which is slowly gaining prominence in the field.

The study revealed some surprising trends. As the corrected insulin response increased, there was a noticeable worsening in waist circumference, HDL (good cholesterol) levels, inflammation and insulin resistance – as long as one did not consider accompanying factors. However, these seemingly negative trends were accompanied by better beta-cell function. Beta cells produce insulin and their ability to do so is closely associated with diabetes risk. In other words, the better beta cells function, the lower the risk.

“Our findings do not support the carbohydrate-insulin model of obesity,” said Retnakaran. “We observed that a robust post-challenge insulin secretory response – once adjusted for glucose levels – is only associated with the beneficial metabolic effects.”

“Not only does a robust post-challenge insulin secretory response not indicate adverse cardiometabolic health, but rather it predicts favorable metabolic function in the years to come.”

In the long run, higher corrected insulin response levels were linked with better beta-cell function and lower glucose levels, without correlating with BMI, waist size, lipids, inflammation or insulin sensitivity and resistance. Most importantly, women who had the highest CIR had a significantly reduced risk of developing pre-diabetes or diabetes in the future.

“This research challenges the notion that high post-meal insulin levels are inherently bad and is an important step forward in our understanding of the complex roles insulin plays in regulation of metabolism,” said Anne-Claude Gingras, director of LTRI and vice-president of research at Sinai Health, who is also a professor of molecular genetics at Temerty Medicine.

Retnakaran hopes the team’s findings will reshape how medical professionals and the public view insulin's role in metabolism and weight management.

“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal. But it’s not that simple,” he said.

The research was supported by grants from the Canadian Institutes of Health Research.