Bacterial regulation of intestinal antimicrobial defense

肠道抗菌防御的细菌调节

• 批准号: 7241504
• 负责人: LORA V HOOPER
• 金额: $ 29.29万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7241504
• 关键词: Address; Adult; Bacteria; Bacteroides thetaiotaomicron; Biochemical; Biological; Biological Models; C-Type Lectins; Cell Communication; Development; Disease; Epithelial; Family; Future; Gene Expression; Genes; Genetic Transcription; Germ-Free; Goals; Health; Human; Individual; Intestines; Laboratories; Lead; Microarray Analysis; Modeling; Modification; Molecular; Mucosal Immune Responses; Mus; Natural Immunity; Paneth Cells; Pattern; Pattern recognition receptor; Play; Population Heterogeneity; Property; Protein Family; Proteins; Regulation; Research Personnel; Role; Shapes; Signal Transduction; System; Toll-like receptors; Weaning; Work; angiogenin; antimicrobial; commensal microbes; critical developmental period; defined contribution; design; in vivo; in vivo Model; insight; laser capture microdissection; member; microbial; microorganism interaction; novel; novel strategies; postnatal; programs; research study; response

DESCRIPTION (provided by applicant): The nonpathogenic intestinal flora play critical roles in human health and disease, yet very little is known about how commensal microbes communicate with their mammalian hosts to establish mutually beneficial relationships. To study these relationships, we use an in vivo system in which germ-free mice are colonized with Bacteroides thetaiotaomicron, a predominant member of the intestinal flora in mice and humans. Laser capture microdissection and microarray analysis have established that B. thetaiotaomicron regulates the transcription of genes encoding antimicrobial proteins in Paneth cells, a small intestinal epithelial lineage specialized for antimicrobial defense. Moreover, changes in Paneth cell antimicrobial gene expression that are normally associated with the weaning transition can be elicited by bacterial colonization of adult germ-free mice, suggesting that commensal bacteria play an instructive role in the development of the Paneth cell antimicrobial arsenal. These results have led to the hypothesis that commensal gut bacteria shape intestinal antimicrobial defense and mucosal barrier function by modulating Paneth cell gene expression. Three specific aims are proposed to address this hypothesis. Aim 1 will characterize the expression patterns of bacterially-regulated Paneth cell antimicrobial genes during postnatal development and in response to microbial factors. Aim 2 will examine the contributions of host pattern recognition receptors, including Toll-like receptors and Nod proteins, to bacteria-Paneth cell interactions. Aim 3 proposes to investigate an antimicrobial function for a member of the Reg family of proteins which is strongly induced in Paneth cells by interactions with commensal bacteria. Together, these studies will yield novel insights into how commensal bacteria shape gut epithelial innate immunity, and will lead to a better understanding of the molecular mechanisms underlying bacteria-epithelial interactions in vivo. Furthermore, this work will aid in designing novel strategies for strengthening the role of the microflora in enhancing the mucosal barrier.

描述（由申请人提供）：非对照性肠道菌群在人类健康和疾病中起关键作用，但对于共生微生物如何与哺乳动物宿主交流以建立互惠互利的关系知之甚少。为了研究这些关系，我们使用了一个体内系统，在该系统中，无菌小鼠与杀菌剂Thetaiotaomicron一起定居，这是小鼠和人类肠菌群的主要成员。激光捕获的显微解剖和微阵列分析已经确定，thetaiotaomicrons调节泛细胞中编码抗微生物蛋白的基因的转录，这是一种专门用于抗菌防御的小肠上皮谱系。此外，通常与成年无菌小鼠的细菌定植相关的泛细胞抗菌基因表达的变化可以引起与断奶过渡相关的变化，这表明共生细菌在Paneth Planeth细胞抗菌药物的发展中起着启发性的作用。这些结果导致了一个假设，即共生肠道细菌通过调节泛细胞基因表达来形成肠道抗菌防御和粘膜屏障功能。提出了三个具体目标来解决这一假设。 AIM 1将表征在产后发育期间细菌调节的Paneth细胞抗菌基因的表达模式，并响应微生物因子。 AIM 2将检查宿主模式识别受体的贡献，包括Toll样受体和NOD蛋白对细菌 - 细菌相互作用的贡献。 AIM 3建议研究蛋白质家族成员的抗菌功能，该抗菌功能通过与共生细菌相互作用在Paneth细胞中强烈诱导。这些研究将共同​​对共生细菌如何塑造上皮先天免疫，并可以更好地理解体内细菌 - 细菌 - 上皮相互作用的分子机制。此外，这项工作将有助于设计新的策略，以增强菌群在增强粘膜屏障中的作用。