Study explores the effects of arsenic on innate immunity and the element’s role in cystic fibrosis
The effects of low levels of arsenic — like those in drinking water — on a healthy innate immune response and one compromised by the gene mutation that causes cystic fibrosis will be the focus of research at the University of Maine funded by a $1.8 million grant from the National Institutes of Health.
The research by UMaine immunologist Carol Kim is part of an $11 million NIH grant to Dartmouth Medical School. The principal investigator is Jason Moore, a computational geneticist at Dartmouth Medical School.
The new NIH project draws on the strength of two major milestones in Kim’s lab — the development of a zebrafish model for studying cystic fibrosis, funded in 2005 with a more than $405,000 NIH grant; and a 2007 discovery that showed that arsenic exposure at levels deemed safe in drinking water suppressed the overall innate immune health in zebrafish, causing increased susceptibility to viral and bacterial infections.
“Particularly in Maine and New Hampshire, as well as across the country, arsenic contamination — both naturally occurring and human-produced pollution — in well water is a problem,” says Kim, director of UMaine’s Graduate School of Biomedical Sciences who has been conducting research on innate immunity and infectious diseases using zebrafish since 1998. “We’re trying to understand how arsenic exacerbates cystic fibrosis and the extent to which this effect is brought about by exposure to arsenic as an environmental toxicant.”
Cystic fibrosis is the most common, fatal genetic disease in the United States, according to NIH’s National Human Genome Research Institute. An estimated 30,000 people in the U.S. have the disease, which is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR). Approximately 10 million Americans carry the defective CFTR gene.
In normal cells, the CFTR protein serves as a channel, allowing cells to release chloride and water into the lungs. However, in people with cystic fibrosis, the protein is defective and the cells do not release the chloride, resulting in an improper salt balance and less water on the lung surfaces, producing abnormally thick mucus.
The gene mutations cause increased susceptibility to Pseudomonas aeruginosa, a common bacterium in water and soil. P. aeurginosa is the cause of chronic infection and irreparable lung tissue scarring in 80 percent of cystic fibrosis patients in their late teens, Kim says. Yet the bacterium is not a common lung pathogen in people with healthy immune systems.
Kim’s research has shown that the zebrafish’s ability to resist bacterial and viral infection is compromised by exposure to arsenic, a naturally occurring element. The effects of arsenic on CFTR and disruption of innate immune response presents a complex, multifaceted puzzle of gene-environment interactions.
The hypotheses are that arsenic disrupts CFTR expression and proteins on the surfaces of certain cells called toll-like receptor (TLR) signal pathways, altering the innate immune response. Kim hopes to identify genes and pathways involved in modulating innate immunity in response to arsenic exposure, as well as CFTR modulation. Her data will be shared with a Dartmouth-based biostatistician and a bioinformatics specialist in an attempt to help identify sets of human genes and signaling pathways that contribute to the innate immune response, respond to arsenic and are influenced by CFTR.
The result could point to potential therapeutic targets.
“This opportunity for scientific collaboration is very exciting,” says Kim. “There is real potential to find genes associated with CF and to identify potential drug targets that could reduce or eliminate many of the debilitating effects of the disease.”
With the NIH grant, Dartmouth Medical School will establish an NIH Center of Biomedical Research Excellence to advance biomedical research and foster collaboration among scientists from UMaine, Harvard, The Jackson Laboratory, Mount Desert Island Biological Laboratory, Maine Medical Center, University of New Hampshire, University of Southern Maine and University of Vermont.
Kim heads one of the first four research projects of the new Center of Biomedical Research Excellence.
Contact: Carol Kim, (207) 581-2803