New Mouse Models of Paneth Cell Defensin Function

描述(申请人提供)：胃肠道的免疫系统保护宿主免受病原体入侵，同时促进不同的、共生的微生物群的定居。对调节这种微妙平衡的机制缺乏明确的了解，但特殊的分泌上皮细胞，称为潘氏细胞，似乎是重要的贡献者。大量证据支持潘氏细胞功能缺陷会增加对肠道病原体和慢性炎症性肠病的易感性。α-防御素是Paneth细胞中含量最丰富的效应分子，对宿主防御和动态平衡都有贡献，但它们在这些过程中的确切功能和贡献尚不完全清楚。这项建议的目标是开发创新的新小鼠模型，作为描述Paneth细胞α-防御素对体内平衡和宿主防御的相对大小和特定贡献的有价值的工具。这些模型将使我们能够检验两个相互关联的假设：(I)Paneth细胞α-防御素是肠道与微生物区系的动态平衡和宿主对肠道细菌病原体防御的主要贡献者，以及(Ii)两个人的α-防御素HD5和HD6在小肠先天性免疫中具有非多余的作用。Aim#1将开发一种新的Paneth细胞α-防御素基因敲除模型，该模型克服了现有模型的局限性。利用这个模型，我们将研究Paneth细胞α-防御素对定植微生物区系的基线组成和对肠道病原体的敏感性的特殊贡献。目的#2将通过分析在缺乏内源性小鼠α-防御素的情况下表达这些防御素生理浓度的转基因小鼠，阐明HD5和HD6在宿主抵抗肠道病原体中的非冗余作用。通过用新的和创新的小鼠模型研究Paneth细胞α-防御素的功能，拟议的研究将对肠道固有粘膜免疫产生洞察力。

DESCRIPTION (provided by applicant): The immune system of the gastrointestinal tract protects the host from pathogen invasion, while facilitating colonization of a diverse, symbiotic microbiota. A clear understanding of the mechanisms that regulate this delicate balance is lacking, but specialized secretory epithelial cells, called Paneth cells, appear to be important contributors. Abundant evidence supports that defect in Paneth cell function increases susceptibility to enteric pathogens and to chronic inflammatory bowel disease. Alpha-defensins are the most abundant effector molecules of Paneth cells and contribute to both host defense and homeostasis, but their precise functions and contributions to these processes are not fully known. The objective for this proposal is to develop innovative new mouse models that will serve as valuable tools to delineate the relative magnitude and specific contributions of Paneth cell alpha-defensins to homeostasis and host defense. These models will enable us to test two interrelated hypotheses: (i) Paneth cell alpha-defensins are major contributors to both intestinal homeostasis with the microbiota and host defense against enteric bacterial pathogens, and (ii) the two human ¿-defensins, HD5 and HD6, have non-redundant roles in small intestinal innate immunity. Aim #1 will develop a novel Paneth cell alpha-defensin knockout model that overcomes the limitations of currently available models. Using this model, we will investigate the specific contribution of Paneth cell alpha-defensins on both baseline composition of the colonizing microbiota and susceptibility to enteric pathogens. Aim #2 will elucidate the non-redundant roles HD5 and HD6 in host defense against enteric pathogens through analysis of transgenic mice that express physiological concentrations of these defensins in the absence of endogenous mouse alpha-defensins. By studying Paneth cell alpha-defensin function with new and innovative mouse models, the proposed research will generate insights on intestinal innate mucosal immunity.