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

潘氏细胞及其防御素在桑普回肠炎发病机制中的作用

• 批准号: 7021092
• 负责人: STEVEN M COHN
• 金额: $ 17.07万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021092
• 关键词: Crohn' s disease; cytokine; defensins; disease /disorder model; gastrointestinal epithelium; genetic regulatory element; genetic strain; hyperplasia; ileitis; ileum; inflammation; laboratory mouse; neutralizing antibody; pathologic process

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.

最近的研究强调了先天免疫在克罗恩病（CD）发病机制中的重要性。潘氏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。潘氏细胞还通过产生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。最近发现NOD 2（一种与CD易感性密切相关的基因）在回肠Paneth细胞中高度表达，也揭示了Paneth细胞对CD发病机制的潜在重要性。我们在SAMP 1/Fc小鼠（一种类似于人CD的回肠炎的自发模型）中的初步研究表明，疾病活动区域的潘氏细胞和中间细胞显著扩增。该建议的中心假设是潘氏细胞通过不适当或持续的促炎介质或通过独特的肠道菌群塑造在CD的肠道炎症发病机制中发挥作用 与未受影响的群体不同的组合物或两者。该提案的具体目的是：目的1）确定SAMP 1/Fc小鼠回肠中潘氏/中间细胞数量增加的机制。将研究腔植物群和炎性细胞因子对分泌细胞增生的发生的贡献以及增生与决定疾病易感性的遗传位点的关联;目的2）确定在SAMP 1/Fc小鼠中由Paneth/中间细胞产生的防御素和相关肽的表达是否改变以及它们在回肠炎发病机制中的作用。回肠潘氏细胞防御素和相关基因的表达将在RNA和蛋白质水平上表征。一个有针对性的基因破坏策略将被用来检查它们在疾病发病机制中的作用; 目的3）明确潘氏细胞和中间细胞在回肠炎发病中的作用。上皮细胞谱系消融方法将用于这些功能研究。