The entire genome of humans has been sequenced, but we still don’t know everything about every gene. Genes sometimes accumulate many names over years as they pass in and out of research labs and the exact characteristics and functions of various genes remains relatively unknown. New research is now shedding light on one such gene, known as Gpr182, and also known as G10D, HrhAMR, Gamrh, 7TMR, and ADMR. It is a receptor that is important in cellular signaling, a G-protein coupled receptor; one place it resides is the surface of special intestinal cells. This research, published in the Journal of Clinical Investigation, may also aid in the development of cancer therapeutics.
"What makes this so exciting is that it's completely new," commented research leader Kathleen Caron, PhD, Professor and Chair of the Department of Cell Biology and Physiology at the UNC School of Medicine. "There was absolutely nothing known about this protein. I think these findings will be picked up on quickly, and I imagine it's going to fuel a lot of research on this receptor now."
Caron became interested in learning more about Gpr182 because it was thought to be a receptor for adrenomedullin, a hormone postulated to be involved in heart function, a focus of Caron’s research. It turns out that Gpr182 isn’t the receptor for that hormone. It took a transgenic mouse with a reporter tag to reveal more about its function.
"Of all the names it had over the years, the name that stuck was adrenomedullin receptor, or ADMR," said Caron, a member of the UNC Lineberger Comprehensive Cancer Center. "It sort of hung that way in the databases for a while, even as science moved forward and scientists found another receptor that is considered to be the real adrenomedullin receptor. A few labs looked at this protein and sort of scratched their heads, because it wasn't really doing what an adrenomedullin receptor should be doing. And then everyone sort of dropped it for a good dozen years."
The researchers were able to detect GPr182 on cells of the heart, lung and kidneys, and importantly, in cells of the undulating lining of the small intestine, the intestinal crypt. That is where the investigators put their focus. "In my undergraduate experience I had been in a gastrointestinal lab, and seeing that position within the intestinal crypt really sparked my interest," said Daniel Kechele, PhD, then a graduate student in Caron's lab, now a postdoctoral fellow at Cincinnati Children's Hospital. "My gastrointestinal background and the strong intestinal stem cell group at UNC made it possible to follow that lead and see where it would take us."
The cells of the crypt experience an incredible degree of turnover, producing 100 square feet of cells and fully replacing the intestinal lining every seven days or so. That high rate of proliferation, required to reduce the risk of infection, raises the chance of tumor growth. Kechle was intrigued by the role that Gpr182 might have in the balancing act played in intestinal proliferation.
Collaborators with expertise in studying the gene activity of intestinal stem cells came in to delve deeper. This tool opened up a whole new world," said Scott Magness, PhD of UNC. "All of a sudden we can use it to figure out how various genes of interest, like Gpr182, are expressed in both active and reserve stem cells, and how the gene might be functioning."
Their work showed that suppressing Gpr182 generally increased proliferation, and suggested that Gpr182 was acting as a brake on cell growth. "We don't necessarily think this gene is itself a driver of cancer, but it's possible that mutations in the gene could play a role in the severity of the cancer," explained Kechele.
When the scientists utilized a sort of chemotherapy model, ablating the active cells of a mouse intestine with radiation, reducing Gpr182 caused a huge increase in growth out of what was left of the stem cell population.
"That suggests this gene could be a target for therapy to speed up the regeneration of the gut lining after cancer treatment," said Magness. "By decreasing the expression of the Gpr182 protein, you might be able to induce the stem cells to respond more robustly in the regenerative phase, thus allowing doctors to use a higher or more effective therapeutic dosage without harming the normal functioning of the gut."
The researchers also looked at human patients; there was less Gpr182 in the colons of colorectal cancer patients compared to healthy colons. A similar decrease was confirmed in other types of cancer as well including breast and lung disease.
Gpr182 is being pursued as a drug target; the company Omeros claims to have a small molecule that is able to interact with Gpr182. The findings are certainly worth exploring as a new avenue for cancer therapeutics.
"I think it shows how passion and grit can really drive science in new and unexpected ways," said Caron. "It takes perseverance to keep asking questions and exploring things. If we had kept on assuming this was an adrenomedullin receptor, we would be missing the mark--and might have missed this exciting breakthrough."
You can see a talk from Dr. Caron in the video above, UNC - Chapel Hill presents "Genetic Research Tools for the Study of the Lymphatic Vascular System."