Saturday, April 5, 2025
4/5/2025
Paneth cell heterogeneity in infection and inflammation - PROJECT SUMMARY Crohn’s disease (CD) is a form of IBD that commonly involves small intestine, where the majority of Paneth cells reside. As a great number of CD patients show no response or refractory to standard treatment, there is an unmet need for new therapeutic options based on new mechanisms of action. Recent studies suggested that defective Paneth cells may play the key role in initiating inflammation in ileal, and maybe ileocecal CD. Paneth cells in CD patients or mouse IBD models often exhibit granule phenotypes characterized initially by Dr. Ta- Chiang Liu, where several Paneth cell-enriched antimicrobial factors, instead of being packed into secretory granules, are dispersed to the cytoplasm. Hypotheses relating to defective ER stress, autophagy, and secretion have been developed to interpret these CD Paneth cell defects, however the cause-and-effect relationship remains obscure. To date, existing studies has been treating Paneth cells as a homogeneous population. Based on a newly developed temporally controlled Paneth cell reporter mouse model, we establish single cell transcriptomic maps for ileal Paneth cells in homeostasis, dysbiosis, infection and inflammation conditions. We found that there is a profound change in Paneth cell heterogeneity in response to microbiota alteration, infection, and potentially genetic risk factors. Analyzing Paneth cell populations across different conditions revealed an immunologically activated Paneth cell subset that has distinct antimicrobial peptide profile, enriched cytokine receptor, and heightened innate immune and degranulation activities. Paneth cells carrying the signature markers are found in ileal CD and UC metaplastic lesions. We will test the hypothesis that a dynamic Paneth cell heterogeneity regulated by interactions of genetic, gut microbiota, and environmental factors such as pathogen infection is critical for activation of Paneth cell-mediated innate protection against inflammatory induction and aggravation. Aim 1 will determine the function and disease relevance of these Paneth cells by examine their innate immune function, degranulation capacity, chromatin and epigenetic profile, in vivo role of specifically secreted mucosal pentraxins, and relevance to CD Paneth cell defects and clinical outcomes. Aim 2 will test how two Paneth cell intrinsic pathways and CD dysbiotic microbiota affect Paneth cell heterogeneity, by performing Paneth cell specific genetic ablation and overexpression, as well as fecal microbiome transplantation in newly developed germ-free Paneth cell reporter mice. This proposal addresses a significant and innovative hypothesis relating to Paneth cell heterogeneity that may contribute to the causality and mechanism of Paneth cell-driven CD pathogenesis. Once a new mechanism regulating proper Paneth cell activation and inflammatory protection is identified, it may be leveraged for IBD intervention.
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