Groups and Projects

Prof. Eran Elinav

Our group studies how host-microbiome interactions affect health and disease. We base our studies on our recently discovered NLRP6 inflammasome, a master intestinal epithelial cell regulator of microbiome composition and function (Cell 2011). We recently described that NLRP6 inflammasome deficiency-associated microbiota alterations (‘dysbiosis’) induce a dramatic propensity for the development of inflammatory bowel disease (IBD), extra-intestinal liver complications such as non-alcoholic fatty liver disease (Nature 2012) and IBD-associated colorectal cancer (PNAS 2013). Intriguingly, microbiota-induced IBD alterations were reversible upon antibiotic treatment and transferable upon transfer of the microbiome configuration between mice. In our current studies we focus on (A) the individualized effects microbiota alterations on development of IBD and its diverse manifestations in mice and human patients (B) Novel innate immune sensing mechanisms regulating the microbiota and the propensity for development of IBD (C) novel cellular subsets orchestrating intestinal homeostasis and regulation of auto-inflammation. In our studies, we combine state of the art immune, microbiological, computational and metabolic research platforms, and take advantage of in-house technologies aimed at high throughput dissection of host and its microbiome, including next generation sequencing, metabolomics, germ-free and anaerobic facility. Altogether, we aim to decipher how host and commensal interactions participate in the pathogenesis of IBD, in an aim to recognize novel molecules that participate in this interaction that may be used as therapeutic targets.

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Excessive responses to the microbial content of the gut contribute to the development of IBD. Key cells that regulate the immune response to gut bacteria are dendritic cells (DCs). Dr. Shakhar’s group studies how DCs sample antigens from the colon and interact with colitogenic bacteria. They believe that interfering with this sampling process could prevent DCs from maintaining inflammatory colitis. The lab has identified two potential sets of molecules that can act as clinical targets and showed that interfering with their function prevents DCs from identifying the colitogenic bacteria and moving towards them, thwarting the sampling process. They have also shown that eliminating a population of DCs marked with the membranal molecule CD103+ reduces activation of potentially colitogenic T cells in the mesenteric lymph nodes that drains the gut.

Prof. Idit Shachar

The progress in understanding the mechanisms of T-cell trafficking, migration and homing, as well as towards the development of mechanisms for the inactivation of these events have been translated into treatment strategies of autoimmune diseases. Our ongoing studies focus on the analysis of pathways that restrict homing of T cell homing, and thereby fine-tune the immune response at specific lymphoid and peripheral tissues. We characterized two pathways that limit T cell migration impairing of lymphocyte homing to peripheral lymph nodes resulting in attenuated progression of inflammation like in various models, including IBD. We now focus on key molecules involved in this homing regulation, in an attempt to develop reagents that will block their function. 

Prof. Ido Amit

ido.amit@weizmann.ac.il ext phone 3338

The involvement of large non-coding RNA in inflammatory bowel diseases

 

Toll Like Receptor (TLR) signalling is one of the major pathways for detection of pathogens in mammals. Misfunction in the TLR pathway is also a main reason for multiple inflammatory related diseases, such as the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis. Detailed understanding of the molecular events that control the TLR pathway will increase our understanding of disease immune- pathogenesis as well as identify targets for therapy at different disease stages. Recently, large non-coding RNA’s (lncRNA) have been shown to be involved in epigenetic regulation of various malignancies. In this proposal, we will characterize the involvement of lncRNA in regulating the TLR pathway and the expression of lncRNA in IBD patients vs. normal controls. Thus dissecting the role of lncRNA of the TLR pathway in the pathogenesis of IBD.

 





Fig. 1. Novel TLR regulated lncRNA found using high throughput genomic tools. A Shown is a new lncRNA in chromosome 1.RNA-Seq and ChIPseq of DC stimulated for 0,1, 2, 4, 6 hours with LPS, mRNA read coverage (blue) , ChIPseq for K4me3 (green), ChIPseq for Stat1 or Stat2 (red),ChIPseq for JunB (dark green). ChIPseq for Rela (blue) B. RNA insitu hybrydization of the lncRNA and TNF before and after LPS stimulation

 

Prof. Irit Sagi

irit.sagi@weizmann.ac.il ext phone 2130

The versatility in the function of ECM bioactive molecules (cytokines, cell-adhesion molecules and receptors) redefines our views on the roles of matrix remodeling enzymes, and underscores the idea that mucosal ECM proteolytic reaction mechanisms represent master switches in the regulation of critical biological processes and instructing cell behavior in inflammation. ECM enzymes such as MMPs are increasingly recognized to play both a physiological role in intestinal homeostasis as well as a pathogenetic role in the initiation and perpetuation of intestinal inflammatory response. These enzymes are the predominant proteases involved in the pathogenesis of IBD via their influence on the function and migration of inflammatory cells, mucosal ulceration, as well as matrix deposition and degradation. Thus, MMPs are extremely pleiotropic and aside from digesting the mucosal ECM, they also target a wide range of other extracellular signaling molecules, including cytokines, growth factors and receptors. We developed novel endougenous-like selective anti-MMP inhibitory antibodies for controlling intestinal inflammation and tissue damage resulting from divergent inflammatory pathways (Sela-Passwell, Nature Medicine 2012). These antibodies opened up new opportunities to both target and study the role of individual matrix enzymes in relevant IBD animal models and human tissues. Current efforts are focused on characterizing the role of microbiome composition in activating destructive ECM remodeling during IBD pathiophysiological processes.

Prof. Rotem Sorek

The Sorek laboratory studies the dynamics of phage attacks and phage resistance among bacteria that inhabit the human gut in Crohn/IBD and normal patients. The team is testing the hypothesis that part of the shift in the gut microbial population that is observed in IBD patients, is connected to bacteriophages that attack gut bacteria.

Prof. Steffen Jung

s.jung@weizmann.ac.il ext phone 2787

Efforts of the Jung laboratory focus on defining differential contributions of intestinal mononuclear phagocytes, including monocytes, dendritic cells and macrophages, in steady state, as well as acute and chronic bowel disorders caused by pathogen challenge (Citrobacter rodentium), irritant exposure (DSS) or genetic predispositions (IL10 deficiency). A particular focus is given to the fates of monocytes in the intestine and the mechanisms that govern their differentiation into non-inflammatory CX3CR1+ macrophages.

 

Prof. Yoram Groner

Runx3 transcription factor is a key hematopoietic gene expression regulator. In the murine gastrointestinal tract (GIT) Runx3 is highly expressed in leukocytes but not in the GIT epithelium. Previously, we found that Runx3-/- mice spontaneously develop inflammatory bowel disease (IBD) and have shown that Runx3 is required for the development and function of dendritic cells (DC). Given that DC play crucial role in mucosal immunity we have generated DCRunx3-/- mice and demonstrated that these mice develop IBD with characteristics similar to those observed in Runx3-/- mice. We thus established DCRunx3-/- mice as an attractive and highly specific model recapitulating the hallmarks of human IBD underscoring the importance of Runx3 in DC-mediated GIT homeostasis. We currently use the DCRunx3-/- mouse model to elucidate the molecular mechanisms underlying IBD development due to lack of Runx3 in lamina propria DC.

Prof. Zelig Eshhar

Malfunction of regulatory T cells (Treg's) is associated with IBD. The Eshhar group has developed means to generate antigen-specific Treg's and provided evidence that adoptive transfer of such genetically modified cells can cure acute colitis.  Ongoing research  focuses on studying the role of Treg's in IBD and on the design and application of redirected Treg's for the suppression of autoimmune chronic colitis and the treatment of ensuing colorectal tumors.