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New Study Illuminates Protein Organization in Cystic Fibrosis Treatment

A recent investigation conducted by researchers at The Hospital for Sick Children (SickKids) sheds light on the mechanisms of protein organization within cell membranes, a finding that holds promise for the development of new treatment strategies for cystic fibrosis.

Cystic fibrosis (CF) is a hereditary disease predominantly affecting the respiratory and digestive systems, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Currently, around 700 genetic variants associated with CF have been identified, though only a limited number of existing therapies target these variations, and none provide a definitive cure.

“We’ve reached a stagnation point in cystic fibrosis treatments, which prompts a need for innovative approaches to understand the biological mechanisms at play. Through our analysis of protein organization, we have opened up new potential pathways for cystic fibrosis therapeutics,” asserts Dr. Jonathon Ditlev, a Scientist in the Molecular Medicine and Cell & Systems Biology programs.

Understanding CFTR Protein through Phase Separation

The study, published in Proceedings of the National Academy of Sciences (PNAS), shifts the focus from the functionality of the CFTR protein to how these proteins are arranged on the cell membrane. In healthy individuals, CFTR proteins cluster together, vital for regulating the balance of water and salt. However, this clustering is impaired in patients with cystic fibrosis.

The formation of protein clusters operates through a mechanism known as phase separation, a concept gaining recognition for its significance in biological organization. Dr. Julie Forman-Kay, who leads the Molecular Medicine program and co-authored the study, suggested in 2017 that this process might be crucial for CFTR function.

“Our research identifies CFTR as a protein that undergoes phase separation, thereby introducing an entirely new perspective on protein regulation and a potential target for developing future therapies,” comments Forman-Kay.

Advancing Cystic Fibrosis Treatments

The investigative team is collaborating with fellow SickKids researchers, including Dr. Christine Bear, a Co-Director of the Cystic Fibrosis Centre, to explore avenues for translating their findings into groundbreaking therapies for cystic fibrosis.

“While the existing therapies are effective for many children, they do not work for everyone,” mentions Bear, also a Senior Scientist in the Molecular Medicine program. “This research could illuminate strategies to benefit those who do not respond to current treatments and improve overall outcomes for individuals affected by CF.”

As this study may contribute to the evolution of cystic fibrosis therapeutics and further the goals of Precision Child Health at SickKids, Ditlev reflects on his initial intentions upon joining SickKids, which did not initially include a focus on CF research. However, that perspective shifted quickly.

“Upon becoming part of SickKids, with its rich tradition of impactful research in cystic fibrosis, I recognized how my expertise and resources could be utilized to advance this significant cause,” Ditlev adds.

This research received funding from the Natural Sciences and Engineering Research Council (NSERC), the National Institutes of Health (NIH), and Cystic Fibrosis Canada.

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