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Graduate Conducts Genetic Research to Find Asthma Treatments

Dr. Ronald Panganiban, a USU graduate, works at the Harvard University T.H. Chan School of Public Health, and recently discovered a gene variant that reduces the susceptibility to asthma. (Courtesy photo)
By Christopher Austin

Asthma affects more than 26 million people in the United States, according to the Centers for Disease Control and Prevention. More than 3,500 die each year from the disease that causes wheezing, breathlessness, chest tightness, and coughing from narrowed, swollen air passages and mucous production.

Certain medications offer asthma sufferers some relief, and avoiding the triggers that can cause an attack also help, but there is currently no cure.

Uniformed Services University alumnus, Dr. Ronald Panganiban, is doing critical genetic research to find new ways of treating asthma. Panganiban, who is originally from the Philippines, earned his PhD in Molecular and Cell Biology at USU, under the supervision of Dr. Regina Day.

Earlier this year, Panganiban and his colleagues at the Harvard University T.H. Chan School of Public Health discovered a variant of the gene Gasdermin B that reduces the susceptibility to asthma. That discovery was published online in January 2018 in the Journal of Allergy and Clinical Immunology, and Panganiban was the study’s lead author. In another related research effort, Panganiban is using modern genetic tools to identify factors that prevent endoplasmic reticulum (ER) stress response, a cellular response to build-up of abnormal proteins in the ER organelle (specialized structures within a living cell).

Family taking a photo with a recent graduate in graduation garb
Dr. Ronald Panganiban (center) earned his PhD in Molecular and Cell Biology at USU, under the supervision of Dr. Regina Day. (Courtesy photo)

“[I’m working on a project to] to identify negative regulators of endoplasmic reticulum stress response. We knock out all the genes in the human genome to find what the novel suppressors of ER stress response are,” Panganiban said.

The endoplasmic reticulum is a small organ-like body found within eukaryotic cells (e.g., mammals not bacteria/viruses). It serves many key functions in the cell including the proper folding of proteins made within the cell and the transport of those newly-made proteins. For a protein to be "active", it must be folded correctly so that its 3D form is correct for it to "work". ER stress response is a build-up of these unfolded proteins that do not have the correct three-dimensional structure in order to function correctly. These unfolded proteins include enzymes, cholesterol, neurotransmitters, and more. ER stress response is believed to be associated with the development of many diseases.

Too much accumulated unfolded protein in the endoplasmic reticulum causes a chain reaction in the cell leading to its death (cell death or apoptosis); this is called the ER stress response. A malfunction of the ER stress response can be caused by genetic mutation (accumulated over time when a person ages) or in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Understanding how cells react to ER stress can accelerate discovery of drugs against diseases such as Alzheimer's, metabolic diseases and inflammation.

diagram of healthy and stressed ER
A diagram explaining how ER stress responses can cause accumulation of unfolded proteins, leading to the development of many diseases. (Courtesy diagram)

Panganiban’s research involves using the revolutionary gene editing technique called Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to edit genes of cells. By knocking out individual genes and observing the cell’s response to ER stressors, he hopes to observe which genes protect cells from dying as a result of an accumulation of abnormal or damaged proteins in the endoplasmic reticulum.

“If they are not in their proper structure – or in technical term, properly folded – they can’t function inside the cell. The cell must get rid of these nonfunctional proteins. If they don’t get rid of them they accumulate in the endoplasmic reticulum,” he said. “What the cell will decide to do is mount a cell death response mediated by the ER stress response, also known as the unfolded protein response. I want to find what the genes that prevent cell death or prevent the unfolded protein response are.”