Health

Discovered that protein can affect cystic fibrosis


“We have identified more than 400 proteins associated with healthy or mutant CFTRs, and have shown that some of them have predict changes in a patient’s symptoms and response to treatment. Center for Cell and Molecular Biology at the YU Department of T’s Temerty.

“With a more comprehensive view of the CFTR protein interaction network, we can identify novel drug targets to trigger patient-specific therapies,” says Stagljar.

The journal Molecular Systems Biology published the study results today and put them on the cover of its February issue.

To help identify CFTR-related protein-protein interactions, the researchers developed a new technology based on the platform they designed in 2014. The approach is a high-throughput version of the system. The mammalian membrane bi-membrane hybrid system and it allows the screening of many other types of membrane proteins bound to a specific protein.

“The previous design was array-based and we were only able to screen for about 200 proteins at a time,” said Stagljar, professor of biochemistry and molecular genetics at the U of T. several changes that allow us to screen thousands of protein targets simultaneously, in a synthetic way. ”

Stagljar and his lab used this technology to find several missed proteins, including many membrane proteins that may play a role in CFTR and cystic fibrosis function. Membrane proteins account for about one-third of all proteins in the cell and about 65% of all drug therapeutic targets.

One particularly promising candidate the team found is the protein Fibrinogen 2, which is thought to play a role in hepatitis, liver disease and immune function. The team has shown that upregulation of this protein leads to an increase in CFTR expression in organics – the 3D in vitro model shows how cells interact within an organelle, in this case with patient-derived intestinal tissues.

“We think that the Fibrinogen-like protein 2 is a valuable drug target for cystic fibrosis, and we are now working with collaborators to confirm other proteins that have emerged in this study,” said Stagljar. and in genome-wide association studies”.

About 2,000 known mutations of the CFTR gene can cause the disease, and drug treatments are often tailored based on an individual patient’s genetic profile. Several treatments have shown significant success over the past decade by restoring the function of the CFTR protein. But response to treatment can vary widely, even between patients who share the same mutation.

Stagljar says that while researchers have long suspected that variations in treatment response depend on secondary genetic regulators and environmental factors, the current study suggests that these proteins The physical link to the CFTR is one of those factors.

Two members of the Stagljar lab were the first co-authors of the paper. Dr. SangHyun Lim, a doctoral student in biochemistry at the time of the study, is currently a postdoctoral researcher at Genentech, and senior research associate Dr. Jamie Snider.

Both are instrumental in research, says Stagljar, and shows that the university continues to train and benefit from great research talent. The two worked closely with other labs on the project, notably at the U of T, the Hospital for Sick Children, and the University of Lisbon in Portugal.

“This study represents a breakthrough in proteomics and cystic fibrosis, but it would not have been possible without many of our collaborators,” said Stagljar. “We developed the technology, but we are not experts in cystic fibrosis, physiology and other areas, so we partnered with the best and they made it the best. reality – that’s how science works today.”

Source: Eurekalert



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