Fighting fibrosis – ‘an underestimated killer’ – through discovery science

By Ana Gajic

Researchers at the Keenan Research Centre for Biomedical Science (KRCBS) of St. Michael’s Hospital have discovered how a group of proteins that control a set of genes responsible chronic organ scarring or fibrosis move in and out of the cell’s nucleus. This new knowledge, recently published in Nature Communications, could one day contribute to treating chronic illnesses such as diabetes or kidney disease.

Transcription factors TAZ and YAP are proteins that activate key genes needed for wound healing and regeneration of organs. If these proteins are not well-controlled, they promote fibrosis, which is a disordered healing attempt characterized by the excessive formation of scar tissue.

TAZ and YAP have to move into the nucleus to unlock genes in DNA. Unravelling how TAZ and YAP move in and out of the nucleus will help to understand and alter their function.

Dubbed an “underestimated killer” by Dr. Andras Kapus, lead author of the research and Director of Trauma, Critical Care and Inflammation at KRCBS, fibrosis is a major cause of lasting and progressive tissue damage in a variety of common chronic illnesses such as diabetes, liver cirrhosis, kidney disease and hypertension. According to current estimates, 45 per cent of people in North America and Europe die of some form of fibrotic disease.

Led by Dr. Kapus and spearheaded by Dr. Michael Kofler, a senior post-doctoral fellow in the Kapus lab, the team set out to track how these factors move in and out of the cell’s nucleus.

“There are pores in the nucleus, and some factors can just go through them; but there are specific carrier systems as well, which act as ferries and provide regulated import or export for proteins,” said Dr. Kapus.

His team’s research showed that TAZ and YAP require such regulated transport to move in and out of the nucleus. This means they contain special segments that direct them to do so – similar to a postal code, Dr. Kapus explained.

“We were able to identify the postal codes both for import and export,” he said. “This is important because when we have the postal code, we can change it, we can inhibit it, or we can rewrite it. In theory, this means we can turn on or off the genes they control, and that we could – at some point – influence cancer and fibrosis.”

Dr. Kapus, Dr. Kofler and their team hope that this knowledge will be used in the future to cure, lessen or even reverse abnormal scarring in chronic conditions.

As it often does, this important discovery led to further questions, Dr. Kapus explained.

“We would like to better define the postal code involved in this transport, and find out how mechanical stimuli and other stresses help these molecules into the nucleus,” he said. “We would also like to build new tools to understand the activation process beyond just transport.”

Dr. Kapus credits their success on this discovery – which took more than four years of research – to the strength of the team.

“Following on previous results and ideas by us and others, Dr. Kofler generated a whole set of highly original molecular tools to attack the problem. The constant ‘intellectual ping-pong’ between us was a key element driving our progress.

“Discovery science cannot be done without major dedication and psychological resilience. I’m proud of our team and our dedication to solving problems. Stimulating discussions make the often painstaking process of research a fun and highly rewarding experience.”

About St. Michael’s Hospital

St. Michael’s Hospital provides compassionate care to all who enter its doors. The hospital also provides outstanding medical education to future health care professionals in more than 29 academic disciplines. Critical care and trauma, heart disease, neurosurgery, diabetes, cancer care, care of the homeless and global health are among the Hospital’s recognized areas of expertise. Through the Keenan Research Centre and the Li Ka Shing International Healthcare Education Centre, which make up the Li Ka Shing Knowledge Institute, research and education at St. Michael’s Hospital are recognized and make an impact around the world. Founded in 1892, the hospital is fully affiliated with the University of Toronto.

About Unity Health Toronto

Unity Health Toronto, comprised of Providence Healthcare, St. Joseph’s Health Centre and St. Michael’s Hospital, works to advance the health of everyone in our urban communities and beyond. Our health network serves patients, residents and clients across the full spectrum of care, spanning primary care, secondary community care, tertiary and quaternary care services to post-acute through rehabilitation, palliative care and long-term care, while investing in world-class research and education. For more information, visit www.unityhealth.to.