ROLE OF PANETH CELLS AND THEIR DEFENSINS IN THE PATHOGENESIS OF SAMP ILEITIS

近年来的研究强调先天免疫在克罗恩病发病机制中的重要性。Paneth细胞是先天免疫系统的关键细胞臂，分泌多种参与宿主对微生物群反应的蛋白质。Paneth细胞还通过产生TNF、GM-CSF和其他免疫调节肽，在调节适应性免疫应答中发挥积极作用。最近的发现也强调了Paneth细胞对CD发病的潜在重要性，NOD2是一个与CD易感性密切相关的基因，在回肠Paneth细胞中高度表达。我们在SAMP1/Fc小鼠（一种类似人类CD的自发性回肠炎模型）的初步研究表明，Paneth和intermediate细胞在疾病活动区域显著扩增。该建议的中心假设是Paneth细胞通过不适当的或持续的促炎介质或肠道微生物群的独特成型在乳糜泻肠道炎症的发病机制中发挥作用

Recent studies have emphasized the importance of innate immunity in Crohn's disease (CD) pathogenesis. Paneth cells are a key cellular arm of the innate immune system, secreting a variety of proteins involved in the host response to microbiota. Paneth cells also play an active role in regulating the adaptive immune response via their production of TNF, GM-CSF and other immunomodulatory peptides. The potential importance of Paneth cells to CD pathogenesis is also undrelined by the recent finding that NOD2, a gene that is strongly linked to CD susceptibility, is highly expressed in ileal Paneth cells. Our initial studies in SAMP1/Fc mice, a spontaneous model of ilietis resembling human CD, demonstrate marked expansion of Paneth and Intermedate cells in areas of disease activity. The central hypothesis of this proposal is that Paneth cells play a role in the pathogenesis of intestinal inflammation in CD either through the inappropriate or continued elaboration of pro-inflammatory mediators or by a unique molding of the intestinal microflora composition that is different from the unaffected population or both. The specific aims of the proposal are: Aim 1) Determine the mechanism by which the number of Paneth/intermediate cells is increased in the ileum of SAMP1/Fc mice. The contributions of luminal flora and inflammatory cytokines to the genesis of secretory cell hyperplasia and the association of the hyperplasia with genetic loci that determine disease susceptibility will be investigated; Aim 2) Determine whether expression of defensins and related peptides elaborated by Paneth/intermediate cells is altered in SAMP1/Fc mice and their role in the pathogenesis of ileitis. Expression of ileal Paneth cell defensins and related genes will be characterized at both the RNA and protein level. A targeted gene disruption strategy will be used to examine their role in disease pathogenesis; and Aim 3) Determine the functional role of Paneth and intermediate cells in the pathogenesis of ilietis. An epithelial cell lineage ablation approach will be used for these functional studies.