Basic Science Research

Dermot McGovern, MD, PhD, and team are working to understand the profound genetics of IBD. In a genetically heterogeneous group of diseases like IBD, the group is defining the relationships of these genes with each other as well as with their individual or combined functional downstream consequences and effects on disease phenotype. Along with Talin Haritunians, PhD, and Dalin Li, PhD, genomics technology and big data approaches are deployed to define the genetics contributing to disease severity, and response to medical therapies.

Teams working under the leadership of Kathrin Michelsen, PhD, have developed in vivo and in vitro modeling systems to define the biologic consequences of IBD-associated genetic variations. With these techniques, they are furthering their discovery that the gene TNFSF15 and the protein it encodes, TL1A, are not only master regulators of intestinal inflammation. At present, they are investigating the role of TNFSF15/TL1A in Paneth cell and epithelial cell function and the development of severe disease phenotypes and forms of IBD characterized by complications such as fibrostenosis.

Dr. Stephan Targan's team, including Maninder Sidhu, PhD, has shown that TL1A levels can influence regulatory cells, leading to either a proregulatory or a protective mucosal environment. Work in the IBIRI labs on TL1A has led to human testing of blocking this protein as a treatment for IBD. In addition, this team is investigating T cell subsets, such as T follicular helper (Tfh)-like cells, which are particularly aggressive in patients with certain gene variations. Understanding the essential regulatory mechanisms of highly aggressive T cell populations' highly aggressive T cells may suggest novel approaches for managing the subsets of IBD patients in which inflammation is caused by these T cells.

Jonathan Braun, MD, PhD and team investigate the concept of host genetic traits may "gardening" intestinal microbial composition and products that in turn drive the disease phenotype. Their human genetic/microbiome interaction studies are evidence of several classes of microbial metabolites associated with IBD disease status, including select amino acid and bile acid metabolites, and an ecologically disruptive role of microbial nitrogen metabolism in disease activity.

Ivan Vujkovic-Cvijin, PhD, and his team seek to identify gut microbes that spur harmful inflammation in inflammatory bowel diseases (IBD) as well as other human inflammatory diseases. Vujkovic-Cvijin has identified gut microbial signatures that may contribute to HIV-associated inflammatory diseases, immunotherapy responses in the setting of cancer, and various monogenic immune diseases. Vujkovic-Cvijin's Lab is actively seeking to uncover methods by which to modulate the human gut microbiota for therapeutic benefit.

Suzanne Devkota, PhD, and her laboratory group are working to understand the role of the microbiome in IBD. The microbiome refers to the microbial inhabitants of the gastrointestinal tract and their interactions with genes and the immune system. Dr. Devkota's group has discovered that creeping fat provides a mechanism for transporting bacteria into the intestine. Dr. Devkota's group is also studying the effect of diet on the microbiome.

Rivkah Gonsky, PhD, and her team are exploring molecular and epigenetic mechanisms to determine the roles of those mechanisms in the immunopathogenesis of IBD. They have found epigenetic alterations that define a subgroups of patients with IBD. These collaborators have also discovered the molecule RNASET2 is a potential target for therapeutic development and a gene signature that may reveal additional targets.

Robert Barrett, PhD, and his laboratory are using human intestinal organoid technology to learn more about the mechanisms underpinning inflammatory bowel disease (IBD). The current research focus of the Barrett Lab is developing a personalized model of intestinal fibrosis, which is a common and potentially serious complication of IBD. This fibrosis model involves directing induced pluripotent stem cells (iPSCs), generated from affected IBD patients, to form human intestinal organoids and subsequently determining their responses to cytokines associated with this complication. Small microengineered Chip technology will be used to examine how microbes and cell-cell interactions play a role in this process.

Under the leadership of Janine Bilsborough, PhD, this unit is working on a pipeline of potential treatment targets they have discovered, as well those identified by colleagues of IBIRI. Using in vivo and intro modeling for validation, the group is developing new drugs and companion diagnostics to help select the people most likely to benefit from them, leading to subgroup-specific treatment. This unit facilitates the speed application of basic science discoveries to the development of new, highly targeted treatments for individuals with IBD.