Maturation of intestinal innate immunity and NEC

肠道先天免疫和NEC的成熟

• 批准号: 8440837
• 负责人: W ALLAN WALKER
• 金额: $ 30.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-12 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440837
• 关键词: Accounting; Address; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bacteria; Birth; Breast Feeding; Cell Line; Cessation of life; Characteristics; Chronic; Clinical; Complication; Development; Down-Regulation; Elements; Enterocytes; Epithelial; Equilibrium; Etiology; Family; Food; Gastrointestinal tract structure; Glucocorticoids; Growth; Health; Human; Immune; Immune response; Immune system; In Vitro; Incidence; Individual; Infant; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Lead; Lipopolysaccharides; Mediating; Microbe; Modeling; Molecular; Mucositis; Natural Immunity; Necrosis; Necrotizing Enterocolitis; Neonatal Intensive Care; Neonatal Intensive Care Units; Neonatal Mortality; Newborn Infant; Nurseries; Pathogenesis; Pathway interactions; Pattern; Peptidoglycan; Perinatal; Premature Infant; Prevention strategy; Probiotics; Process; Public Health; Receptor Signaling; Regulation; Risk Factors; Role; Signal Pathway; Signal Transduction; Sterility; Steroids; Therapeutic; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Xenograft Model; Xenograft procedure; attenuation; design; feeding; fetal; gastrointestinal epithelium; human TLR8 protein; ileum; in vivo; microbial; neonatal morbidity; novel; premature; prevent; receptor; receptor expression; receptor-mediated signaling; response; steroid hormone

DESCRIPTION (provided by applicant): A family of Toll-Like Receptors (TLRs) stimulates the innate immune system upon encountering microbial pattern molecules, lipopolysaccharide [LPS] or peptidoglycans [PG]. When the gastrointestinal tract is initially colonized by microbes at birth, the mucosal innate immune system requires attenuation to avoid chronic inflammation by activation of TLR pathways. In term infants, perinatal downregulation of intestinal TLRs may provide this attenuation. In premature infants born before this developmental regulation, intestinal colonization could activate TLR pathways, leading to chronic inflammation. An inappropriate immune response to bacterial exposure could lead to generalized inflammation and bowel necrosis, such as occurs in necrotizing enterocolitis (NEC). In this proposal, we will study the ontogeny of TLR receptor expression, signaling, and inhibition, and determine its role in regulating innate immune responses. Steroids and probiotic therapy have been shown to prevent the onset of some premature infants predisposed to NEC. The mechanism of steroid action and the role of probiotic therapy will be determined. The probiotic factors that prevent excessive activation of the gut epithelium by microflora in term infants will be identified. The hypothesis is that colonization of the premature infant gut prior to maturation of the TLR signaling pathway can lead to excessive inflammation of the infant gut characteristic of NEC. The capacity of health-promoting probiotic bacteria to accelerate ontogeny of negative regulators of TLR pathways, thereby preventing excessive inflammation, will be investigated. We have developed specific human in-vivo and in-vitro intestinal models for gut inflammation to address this hypothesis. Our specific aims address whether: (1) coordinated downregulation of TLR receptors and its signaling intermediates and negative regulators prevents excessive inflammatory response to bacterial colonization at birth; (2) pretreatment with glucocorticoids prevents hyperresponsiveness to newly colonizing bacteria by inducing maturation of the TLR signaling pathways in premature gut; and (3) probiotic factors prevent the onset of NEC by accelerating the maturation of the TLR signaling pathways in premature gut. The successful completion of this project will provide novel basic information on the ontogeny of the control elements of TLR signaling pathways, and their modulation by steroids and probiotics. This mechanistic understanding of the effect of steroids and probiotics in preventing inflammation in premature infants could be used to design effective therapeutic strategies to prevent the onset of NEC. This is important since NEC is an important public health issue facing premature infants and accounts for 10% of all deaths in the US.

描述（由申请人提供）：一系列Toll样受体（TLR）家族在遇到微生物模式分子，脂多糖[LPS]或肽聚糖[PG]时刺激先天免疫系统。当胃肠道最初在出生时通过微生物定植，粘膜先天免疫系统需要衰减以避免通过激活TLR途径避免慢性炎症。在期限婴儿中，肠道TLR的围产期下调可能会提供这种衰减。在这种发育调节之前出生的早产婴儿中，肠道定植可以激活TLR途径，导致慢性炎症。对细菌暴露的不当免疫反应可能导致普遍的炎症和肠坏死，例如在坏死性小肠结肠炎（NEC）中发生。在此提案中，我们将研究TLR受体表达，信号传导和抑制的个体发育，并确定其在调节先天免疫反应中的作用。已经证明类固醇和益生菌疗法可以防止某些早产婴儿的发作。将确定类固醇作用的机制和益生菌治疗的作用。将鉴定出益生菌因菌群在病期婴儿中过度激活肠道上皮的过度激活的益生菌因子。假设是，在TLR信号通路成熟之前，早产婴儿的肠道定植会导致NEC婴儿肠道特征过度炎症。将研究TLR途径负调节剂的个体发育，从而预防过度炎症，从而加速了促成健康的益生菌细菌的能力。我们已经开发了特定的人类内部和体外肠道模型，以解决肠道炎症，以解决这一假设。我们的具体目的是解决：（1）TLR受体的协调下调及其信号传导中间体和负调节剂可防止出生时对细菌定植的过度炎症反应； （2）用糖皮质激素预处理通过诱导过早肠道中TLR信号通路的成熟来防止新定植细菌的过度反应； （3）益生菌因素通过加速过早肠道中TLR信号通路的成熟来阻止NEC的发作。该项目的成功完成将提供有关TLR信号通路控制元素的个体发育的新基本信息，以及它们通过类固醇和益生菌的调节。对类固醇和益生菌在预防过早婴儿炎症的影响的机械理解可用于设计有效的治疗策略，以防止NEC发作。这很重要，因为NEC是早产婴儿面临的重要公共卫生问题，占美国所有死亡人数的10％。