Researchers find trove of proteins that may influence cystic fibrosis


Date:
February 14, 2022
Source:
University of Toronto
Summary:
Researchers have identified hundreds of new proteins that could
play a role in cystic fibrosis, and which may shed light on why
some patients respond better than others to current therapies.



FULL STORY ========================================================================== Researchers at the University of Toronto have identified hundreds of
new proteins that could play a role in cystic fibrosis, and which may
shed light on why some patients respond better than others to current therapies.


==========================================================================
Many of these proteins -- part of a group of druggable molecules called membrane proteins -- interact with the CFTR protein, which when missing
or faulty leads to the build-up of mucous in the lungs and other organs
that is often fatal in cystic fibrosis.

"We identified more than 400 proteins associated with either healthy
or mutant CFTR, and have shown that some of them could predict the
variability seen in patient symptoms and treatment responses," said
Igor Stagljar, principal investigator on the study and a professor in
the Donnelly Centre for Cellular and Biomolecular Research at U of T's
Temerty Faculty of Medicine.

"With a more comprehensive view of the CFTR protein interaction
network, we can identify novel drug targets that should enable more patient-specific therapies," Stagljar said.

The journal Molecular Systems Biology published the findings today,
and featured them on the cover of its February issue.

To help identify protein-protein interactions involving CFTR, the
researchers developed a new technology based on a platform they designed
in 2014. The approach is a high-throughput version of their Mammalian
Membrane Two-Hybrid system, and it allows for screening of many more
membrane proteins that associate with a specific protein.



==========================================================================
"The earlier design was array-based, and we could only screen about
200 proteins at a time," said Stagljar, who is also a professor of
biochemistry and molecular genetics at U of T. "With this new technology,
we've introduced several changes that allow us to screen thousands of
protein targets simultaneously, in a pooled manner." Stagljar and his
lab used the technology to find several overlooked proteins, including
many membrane proteins that may play a role in CFTR function and cystic fibrosis. Membrane proteins account for roughly one-third of all proteins
in cells and about 65 per cent of all drug therapy targets.

One especially promising candidate the team found is the Fibrinogen-like
2 protein, thought to play a role in hepatitis, liver disease and immune function. Downregulation of this protein, the team showed, leads to
increased expression of CFTR in organoids -- 3D in vitro models that
show how cells interact in an organ, in this case with patient-derived
gut tissues.

"We think Fibrinogen-like 2 protein is a valuable drug target for cystic fibrosis, and we're now working with our collaborators to validate other proteins that turned up in this study and in genome-wide association
studies," Stagljar said.

Cystic fibrosis affects over 90,000 people globally. The disease can
arise when children inherit two mutated CFTR genes, one from each parent, resulting in defective CFTR proteins on the surface of cells in the
lungs and other organs.



========================================================================== About 2,000 known mutations of the CFTR gene can cause the disease,
and drug treatments are often tailored based on each patient's genetic
profile. Some of those treatments have shown remarkable success in the
last decade by restoring function of the CFTR protein. But treatment
response can vary widely, even among patients who share the same mutation.

Stagljar said that while researchers have long suspected that those
variations in treatment response hinge on secondary genetic modifiers
and environmental factors, the current study strongly suggests proteins
that physically associate with CFTR are one of those factors.

Two members of the Stagljar lab were co-first authors on the paper. Dr.

SangHyun Lim, a biochemistry doctoral student at the time of the study
who is now a postdoctoral researcher at Genentech, and senior research associate Dr.

Jamie Snider.

Stagljar said both were instrumental in the research, and show that the university continues to train and benefit from great research talent. Both worked closely with other labs on the project, in particular at U of T,
The Hospital for Sick Children and the University of Lisboa in Portugal.

"This study represents a breakthrough in proteomics and cystic fibrosis,
but it would have been impossible without our many collaborators,"
said Stagljar. "We developed the technology, but we're not experts
in cystic fibrosis, physiology and other fields, so we teamed up with
the best and they made it happen - - that's how science works nowadays." ========================================================================== Story Source: Materials provided by University_of_Toronto. Original
written by Jim Oldfield.

Note: Content may be edited for style and length.


==========================================================================


Link to news story: https://www.sciencedaily.com/releases/2022/02/220214095749.htm

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