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RNA sequencing plays role in new research funded by Beyond Celiac

August 23, 2019

$420,000 awarded to two ground breaking celiac disease studies

Grant awardees Jocelyn Silvester and Paul Klenerman

By Amy Ratner, Medical and Science News Analyst

Scientists awarded Beyond Celiac research grants totaling $420,000 will conduct two groundbreaking celiac disease studies, one into killer cells that cause the actual tissue damage in the intestine and the other into a more exact way to measure intestinal damage revealed in a biopsy.

The grants are international in scope with one awarded to Paul Klenerman, PhD, a professor of gastroenterology at the University of Oxford, Oxford, England, and the other to Jocelyn Silvester, MD,director of research at the Celiac Disease Program at Children’s Hospital.

T-Cells: White blood cells that function as the body’s disease fighting soldiers and are improperly activated by gluten in those who have celiac disease.

Overall, Beyond Celiac gave top priority in awarding the 2019 grants to additional research into the role of T-cells in driving and diminishing the immune response in celiac disease. Earlier this year, Beyond Celiac also awarded an Early Career grant of $150,000, bringing the total invested in research to about $600,000.

Established Career Award

Klenerman, an immunologist who has done extensive work in Hepatitis C and HIV (human immunodeficiency virus), received the Established Investigator Award, a grant of up to $100,000 for each of three years. The award placed emphasis on immunology and was designed to support new and novel approaches to understanding celiac disease. It also encourages scientists working in another related field, like Klenerman, to turn their attention to celiac disease.

Klenerman’s research will focus on T-cells in the inner gut lining – killer CD8 T-cells. The role of another type of T-cell, the CD4 T-cell, has been more thoroughly studied and scientists know it responds to gluten and plays a key role in celiac disease. Less is known about the T-cells Klenerman will study, though they lead to the myriad of consequences of celiac disease.

“We do not fully know what activates them, how they cause damage and how they can be regulated,” Klenerman said. His work will attempt to answer these questions.

Currently, it’s known that a particular type of CD8 T-cell is abundant in the gut of celiac disease patients even when they are on the gluten-free diet. “These cells have features which suggest they are responding to a particular, unknown signal, and acting to cause inflammation, potentially driving celiac disease,” Klenerman explained.

Ribonucleic acid (RNA): an important biological macromolecule that functions to convert the genetic information encoded by DNA into proteins.

He plans to study “the new and exciting cell type” using several cutting edge techniques, including RNA sequencing, to determine which genes are turned on.

“We believe we have found a new cell type that is driving inflammation and tissue damage in celiac disease,” Klenerman said. “This project will explore the cells role in celiac disease, what triggers them, which may directly lead to improved tests and treatments.

Pilot and Feasibility Award

RNA study will also factor into Silvester’s research as the recipient of the Pilot and Feasibility Award, which is given to help scientists collect the preliminary data needed to begin answering major questions about celiac disease. This type of early phase of study could lead to breakthroughs for larger scale research or clinical trials.

“There is an urgent clinical and research need for improved methods to asses celiac disease activity in small intestinal biopsies,” said Silvester, whose other work in celiac disease research is well known.

RELATED: Watch this video explaining Silvester’s previous work

Currently, celiac disease diagnosis is made through the result of anti-tissue transglutaminase (TTG) testing and the gold standard — evidence of intestinal damage found in a biopsy

“Diagnosis of celiac disease currently relies upon visual inspection of biopsies under the microscope by pathologists using methods that were developed over 50 years ago,” Silvester said.

Transcriptomics:  the study of all the RNA molecules within a cell, otherwise known as the transcriptome.

She said preliminary data show that transcriptomics of intestinal biopsies can identify genes that correlate to inflammation caused by gluten and structural changes in the villi, the absorbing finger-like projections in the intestine.

Her upcoming study will use RNA sequencing of a series of biopsies collected during an earlier gluten-challenge study. Silvester will then check the accuracy of the sequencing method on biopsies previously taken for diagnosis and follow-up on another group of patients.  She will be able to compare biopsies taken when gluten was in the diet and after a gluten-free diet was being followed.

“RNA sequencing is a powerful tool that allows analysis of what a cell is doing at the molecular level,” Silvester said, noting it does not require pre-selecting a particular molecule. “This makes RNA sequencing a very useful platform for discovery because what is most interesting may not be what we thought we were looking for.”

In addition to diagnosis, RNA sequencing could be useful in monitoring changes on a gluten-free diet, according to Silvester. Her proof of concept study will provide essential pilot data to support applications for future funding and to demonstrate the validity of the approach in celiac disease and other conditions in which there is damage to the villi.


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