New Mouse Models of Paneth Cell Defensin Function

描述（由申请方提供）：胃肠道的免疫系统保护宿主免受病原体入侵，同时促进多样化共生微生物群的定殖。对调节这种微妙平衡的机制缺乏明确的理解，但专门的分泌上皮细胞，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-防御素是潘氏细胞中最丰富的效应分子，有助于宿主防御和稳态，但其确切的功能和对这些过程的贡献尚不完全清楚。该提案的目标是开发创新的新小鼠模型，这些模型将作为有价值的工具来描绘潘氏细胞α-防御素对稳态和宿主防御的相对大小和具体贡献。这些模型将使我们能够测试两个相互关联的假设：（i）潘氏细胞α-防御素是肠道内稳态与微生物群和宿主防御肠道细菌病原体的主要贡献者，以及（ii）两种人类防御素HD 5和HD 6在小肠先天免疫中具有非冗余作用。目标#1将开发一种新的潘氏细胞α-防御素敲除模型，克服目前可用模型的局限性。使用该模型，我们将研究帕内特细胞α-防御素对定殖微生物群的基线组成和对肠道病原体的易感性的具体贡献。目的#2将通过分析在不存在内源性小鼠α-防御素的情况下表达生理浓度的这些防御素的转基因小鼠，阐明HD 5和HD 6在宿主防御肠道病原体中的非冗余作用。通过研究潘氏细胞α-防御素功能与新的和创新的小鼠模型，拟议的研究将产生对肠道先天粘膜免疫的见解。 公共卫生相关性：潘氏细胞α-防御素可能具有两种相互关联的基本功能：塑造定植微生物群的组成，并保护宿主免受肠道病原体的侵害。这些功能将对人类健康产生深远的影响。拟议的研究将产生和表征一组互补的新小鼠模型，以研究潘氏细胞α-防御素的功能。

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. PUBLIC HEALTH RELEVANCE: Paneth cell alpha-defensins likely have two interrelated and fundamental functions: shape the composition of the colonizing microbiota, and protect the host from enteric pathogens. These proposed functions would have profound influence on human health. The proposed research will generate and characterize a complementary set of new mouse models to investigate the function of Paneth cell alpha-defensins.