Amoeba biology reveals potential treatment target for lung disease – sciencedaily

In a series of experiments that began with amoeba – single-celled organisms that extend pod-shaped appendages to move around – scientists at Johns Hopkins Medicine say they have identified a genetic pathway that could be activated to help clear mucus lungs of affected people. chronic obstructive pulmonary disease a widespread lung disease.

“Medical scientists and basic biologists have worked together to understand a problem that causes major human disease, and the problem, as often happens, is in basic cell biology,” says Doug Robinson, Ph .D., Professor of Cell Biology, Pharmacology and Molecular Sciences, Medicine (Pulmonary Division), Oncology, and Chemical and Biomedical Engineering at Johns Hopkins University School of Medicine.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, affecting more than 15 million adults, according to the United States Centers for Disease Control and Prevention. The disease causes the lungs to fill up with mucus and phlegm, and people with COPD experience chronic coughing, wheezing, and difficulty breathing. Smoking is the main cause in as many as three-quarters of COPD cases, and there is no cure or effective treatment available despite decades of research.

In a report on their new work, published on February 25 in the Journal of Cell Science, the researchers say they’ve taken a new approach to understanding the biology of the disorder by focusing on an organism with a much simpler biological structure than human cells to identify genes that might protect against harmful chemicals in cigarette smoke.

Robinson and his collaborator, Ramana Sidhaye, MD, also professor of medicine in the Division of Pulmonology at Johns Hopkins, along with their former lab member Corrine Kliment, MD, Ph.D., relied on the knowledge that as they went As species evolved, genetic pathways were frequently retained across the animal kingdom.

Enter the soil amoeba Dictyostelium discoideum, which has long been studied to understand cell movement and communication. Scientists pumped lab-grade cigarette smoke through a tube and bubbled it up in the liquid nutrients bathed in the amoeba. Next, the scientists used engineered amoeba to identify genes that could provide protection against smoke.

Looking at the genes that provided protection, creating “surviving” cells, one family of genes stood out among the rest: adenine nucleotide translocase (ANT). The proteins produced by this group of genes are found in the membrane, or on the surface, of a cell’s energy structure, known as mitochondria. Typically, mitochondria help make the fuel cells use to survive. When an ANT gene is very active, cells become more efficient at making fuel, protecting them from smoke.

Kliment, Robinson, and the team suspected that they were also helping the amoeba overcome the ill effects of cigarette smoke.

To better understand how the ANT genes behave in humans, the scientists studied tissue samples of cells lining the lungs taken from 28 people with COPD who were treated at the University of Pittsburgh and compared the activity genetics of lung cells with cells from 20 people with normal lungs. a function.

Scientists found that patients with COPD had about 20% less gene expression of the ANT2 gene than those with normal lung function. They also found that mice exposed to smoke lost expression of the ANT2 gene.

Then Robinson, Kliment, and their research team set out to find out how ANT2 could provide protection against the chemicals in cigarette smoke, and in doing so, discovered something completely unexpected.

Cells lining the lungs use finger-like projections called cilia to sweep mucus and other particles out of the lungs. In mammals, including humans, scientists have found that the ANT2 gene produces proteins that localize in and around the cilia that work to release tiny amounts of fuel from the cell into a watery substance next to the cell. The fuel improves the ability of the eyelashes to rhythmically and steadily “beat” to sweep away mucus.

“In COPD patients, the mucus becomes too thick to be cleared from the lungs,” says Robinson.

The Johns Hopkins medical team found that, compared to human lung cells with normal ANT2 function, the cilia of human lung cells lacking ANT2 beat 35% less efficiently when exposed to smoke. Additionally, the watery fluid next to the cell was about half the height of normal cells, suggesting the fluid was denser, which may also help reduce beat rates.

When scientists genetically engineered lung cells to have an overactive ANT2 gene and exposed them to smoke, the cilia of the cells beat with the same intensity as normal cells not exposed to smoke. The aqueous layer next to these cells was about 2.5 times taller than that of cells lacking ANT2.

“Cells are effective at reusing cellular processes between species, and in our experiments we found that mammals reused the ANT gene to help provide cellular signals to build the appropriate hydration layer in the airways.” , explains Robinson. “Who would have thought that a mitochondrial protein could also live on the cell surface and be responsible for helping the cilia in the airways to beat and move?”

Robinson says further research could lead to discoveries to develop gene therapy or drugs to add ANT2 function in lung lining cells as a potential treatment for COPD.

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