zebrafish Archives - Sanford Burnham Prebys

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Institute News

Duc Dong honored at Alagille Syndrome Alliance Gala

AuthorSusan Gammon
Date

July 10, 2018

Duc dong

Associate Professor Duc Dong, PhD, was the guest of honor at the Gala of Dreams, the inaugural fundraiser for the Alagille Syndrome Alliance held June 30 at the San Diego Marriott Del Mar. Dong is a trailblazer in the field of Alagille syndrome research—he is working toward a cure for the extremely rare genetic condition that affects approximately one in 30,000 births.

Babies born with Alagille syndrome have too few bile ducts—which are essential for the transport of waste out of the liver. This causes toxins build up in the liver and throughout the body, leading to constant severe itching, and more critically, liver damage and failure. Alagille syndrome patients also have many other life-threatening developmental defects in other parts of their bodies, including the heart, kidneys, vertebrae, and blood vessels. There is no cure for this debilitating disease, and up to 50 percent of patients eventually need a liver transplant, often during childhood.

Dong and his team have been studying JAGGED1, the gene implicated in Alagille syndrome. Taking advantage of an unusual animal model, the zebrafish, he has been able to uncover a novel genetic mechanism for the disease—opening new potential therapeutic avenues. Further, his team has surprisingly discovered that the bile ducts lost can be regenerated after turning the affected gene back “on.”

“The implication is that these developmental defects in Alagille syndrome patients could potentially be reversible and therefore curable,” says Dong. “We will now start screening for drugs that may be used to restore the function of this genetic pathway and hopefully allow for these lost bile ducts to regenerate. We will continue to challenge the science of Alagille syndrome to move closer to a cure.”

The theme of the event, “The Dawn of a Dream,” signified new advances in Alagille syndrome research and the anniversary of the organization’s 25th year in existence. The evening gave advocates, families, doctors and pharma representatives an opportunity to interact in a fun, casual setting and participate in a silent auction to raise money for research. Dong’s lab was presented with the Champion of Alagille Syndrome Award and funds raised by the Alliance through crowd sourcing.

Institute News

Research may explain congenital deafness

AuthorJessica Moore
Date

March 15, 2017

boy with hearing aid

If you’ve heard of hyaluronic acid (HA), it’s probably as an ingredient in cosmetic products meant to help keep skin moisturized. But HA—a polysaccharide, or long chain of sugars—is also a major component of the material that surrounds cells in almost every tissue. It’s particularly important in joints, where it’s part of the fluid that lubricates the cartilage ends of bones as they move against each other, and in the eyes, where it helps maintain the shape of the eyeball.

HA is broken down and replaced much faster than other molecules that make up the structure of tissues—one-third of all the HA in your body (about 15 grams in an average-sized human) is turned over each day. But despite its ubiquity and rapid turnover, how HA is degraded remained a mystery. The only enzymes known to cut it up are located inside cells, but HA is far too large to be taken into a cell whole.

That conundrum has now been untangled. Research from the lab of Yu Yamaguchi, MD, PhD, professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), has identified the enzyme that chops extracellular HA into pieces, a protein called TMEM2 (transmembrane protein 2).

“Until now, the function of TMEM2 was unknown,” says Yamaguchi. “We show that it specifically cleaves HA and none of the other polysaccharides that surround cells.”

The discovery, published in the Journal of Biological Chemistry, could help explain the seemingly unrelated effects of altering or inactivating the TMEM2 gene. Zebrafish lacking TMEM2 die as embryos because their hearts don’t develop properly, and mutations in TMEM2 have been linked to severe inherited deafness. That those presentations are so different is less perplexing now that we know that TMEM2 helps control levels of HA. HA is an important ingredient in cardiac jelly, the gelatinous tissue that fosters proper heart formation, and in the fluid in the inner ear that conducts sound waves.

“Our findings open the door to better understanding of an unknown number of disease states,” Yamaguchi adds. “The fact that eliminating the TMEM2 gene causes mortality suggests that it’s really important, but keeps us from seeing how it supports the function of various tissues later in life. To figure that out, we’re making mice that lack TMEM2 only in certain organs.”