LOS ANGELES–(BUSINESS WIRE)–Investigators at Children’s Hospital Los Angeles, led by Tracy C.
Grikscheit, MD, have mapped the genetic changes resulting from short
bowel syndrome (SBS) using a novel zebrafish model and by performing
intensive gene sequencing. This approach to determining which genes are
markedly over or under expressed in SBS may assist scientists in
developing future therapies for children and adults with this condition.
Results of the study are published in BioMed Central Genomics.
Necrotizing enterocolitis in premature infants, Crohn’s disease in
children and adults and trauma can necessitate the removal of
significant quantities of small intestine resulting in SBS and
subsequently, in the body being unable to absorb nutrition from food
because of an inadequate length of small intestine. In children, the
incidence of SBS is almost double that of childhood cancer and the
mortality rate at 5 years following surgery is approximately 30 percent.
Until now, the morbidity and mortality associated with SBS has been
related to malnutrition and liver fibrosis from intravenous nutritional
products. In this study the researchers sought to determine systemic
effects attributable to the disease process alone.
The research team conducted the study in zebrafish, using a validated
SBS model created in the Grikscheit laboratory. This model allowed the
investigators to study matched samples of small intestine from zebrafish
who had bowel surgery and those who underwent “sham” or control surgery.
According to first author, Kathy A. Schall, MD, “Most studies of SBS
focus on the epithelial cells that line the intestine but this model
allowed us to focus on systemic effects and the associated genetic
alterations responsible for those effects.”
The paper reports that 29 fish had intestinal surgery compared to 28
fish that received sham surgery. After two weeks, a time previously
determined to be associated with maximal stem and progenitor cell
activity, RNA-sequencing analysis was performed. Zebrafish with SBS had
1346 significantly upregulated genes and 678 significantly downregulated
genes compared to sham-operated controls. The upregulated genes were
related to processes that include cell proliferation, acute phase
response signaling, innate and adaptive immunity, bile acid regulation,
production of nitric oxide and reactive oxygen species, cellular barrier
maintenance and coagulation. Downregulated genes were associated with
folate synthesis, gluconeogenesis, glycogenolysis, fatty-acid oxidation
and activation and drug and steroid metabolism.
“We’ve identified marked changes in several metabolic pathways –
including some that had previously been considered an effect of
intravenous nutrition,” said Grikscheit, who is also a tenured associate
professor of surgery at the Keck School of Medicine of the University of
Southern California. “Knowing that these alterations are caused by SBS
in the absence of intravenous nutrition provides us multiple targets for
developing new therapies to modify these effects. Instead of digging in
random places we now have a map to follow in our search for therapeutic
approaches for SBS.” Grikscheit adds that a reduction of just 10 percent
of U.S. patients requiring home intravenous nutrition for SBS would
result in an estimated saving of nearly $800 million in health care
Additional contributors to the study include Matthew E. Thornton, Mubina
Isani, Kathleen A. Holoyda, Xiaogang Hou, Ching-Ling Lien and Brendan H.
Grubbs of The Saban Research Institute of Children’s Hospital Los
Angeles and USC Keck School of Medicine. The study was funded in part by
the 2014 CHLA CIRM Training grant (8236-TCS008566) and the 2015 Broad
Clinical Fellowship sponsored by the Eli and Edythe Broad Foundation
About Children’s Hospital Los Angeles
Children’s Hospital Los Angeles has been named the best children’s
hospital in California and among the top 10 in the nation for clinical
excellence with its selection to the prestigious U.S. News & World
Report Honor Roll. Children’s Hospital is home to The Saban Research
Institute, one of the largest and most productive pediatric research
facilities in the United States. Children’s Hospital is also one of
America’s premier teaching hospitals through its affiliation since 1932
with the Keck School of Medicine of the University of Southern
California. For more information, visit CHLA.org.
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