Gregory F. Sonnenberg, The Henry R. Erle, M.D.-Roberts Family Associate Professor of Medicine and head of basic research in Gastroenterology and Hepatology at Weill Cornell Medicine, has been awarded a five-year, $3.26 million grant from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, to investigate the underlying mechanisms of inflammatory bowel disease (IBD).

The new grant, under the Method for Extending Research In Time (MERIT) program, will fund research on a novel pathway that protects the intestine from damage and inflammation driven by an immune-derived factor called tumor necrosis factor (TNF).

“It’s a huge honor to be considered and nominated for a NIH MERIT award, and such a privilege to be able to move this research forward with my laboratory over an extended period of time,” Sonnenberg said.

The MERIT program gives investigators with stellar records of research accomplishment a five-year award with the possibility of extending the initial award for up to five additional years without the need to undergo another competitive peer review.

Sonnenberg’s proposal was based on research his laboratory pioneered over the past decade characterizing key immune cell pathways in the intestine. It’s one of the major mysteries in the field.

“TNF is normally beneficial, but what causes this shift for it to become a major mediator of chronic inflammatory diseases?” said Sonnenberg, who is in the Division of Gastroenterology & Hepatology in the Weill Department of Medicine and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine.

Many current therapies block TNF to reduce inflammation in chronic inflammatory diseases, including IBD, rheumatoid arthritis and psoriasis, but those treatments are only effective in a subset of patients. And even if successful, this therapy can lose efficacy over time.

Sonnenberg’s team discovered that TNF-induced gut inflammation correlates with the depletion of group 3 innate lymphoid cells (ILC3s), a special class of cells abundant in the healthy intestine. “This provoked a hypothesis that these cells are keeping the TNF molecule in check and stopping it from driving tissue inflammation,” Sonnenberg said.

Experiments published last year in preclinical models confirmed that hypothesis and revealed that ILC3s are essential to protect the intestine from TNF-mediated damage and inflammation, which the team will explore further with support of this MERIT Award. Sonnenberg and his laboratory proposed a series of experiments to define the cellular and molecular signals by which ILC3s protect from TNF-induced inflammation.

He also plans to investigate this pathway in both mouse models and patient-based organoids, which are complex human cell culture systems that model the guts of healthy individuals or patients with IBD.

Researchers cannot apply for MERIT grants directly; Sonnenberg and his laboratory originally applied for a standard “R01” grant from the NIH, which received a fundable score after peer-review and was subsequently nominated by NIH program staff for the MERIT award instead. Each year, NIAID issues about 15 new MERIT awards.

The new award, which can double the length and amount of the grant, will take the investigation further, laying the groundwork for a much deeper understanding of IBD and paving the way for new therapeutic strategies.

Research reported in this story was supported by a grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Alan Dove is a freelance writer for Weill Cornell Medicine.