Maturation of intestinal innate immunity and NEC

描述（由申请人提供）：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。当出生时胃肠道最初被微生物定殖时，粘膜先天免疫系统需要通过TLR途径的激活来减弱以避免慢性炎症。在足月婴儿中，围产期肠道TLR下调可能提供这种衰减。在这种发育调节之前出生的早产儿中，肠道定植可以激活TLR途径，导致慢性炎症。对细菌暴露的不适当的免疫应答可能导致全身性炎症和肠坏死，例如发生在坏死性小肠结肠炎（NEC）中。在这个提议中，我们将研究TLR受体表达，信号传导和抑制的个体发生，并确定其在调节先天免疫反应中的作用。类固醇和益生菌治疗已被证明可以预防一些易患NEC的早产儿的发病。类固醇作用的机制和益生菌治疗的作用将被确定。将确定防止足月婴儿肠道上皮被微生物群过度激活的益生菌因子。假设是在TLR信号传导途径成熟之前早产儿肠道的定殖可导致NEC特征的婴儿肠道过度炎症。将研究促进健康的益生菌加速TLR途径的负调节物的个体发育，从而防止过度炎症的能力。我们已经开发了用于肠道炎症的特定人体内和体外肠道模型来解决这一假设。我们的具体目标是：（1）TLR受体及其信号中间体和负调节因子的协调下调是否可以防止出生时对细菌定植的过度炎症反应;（2）糖皮质激素预处理通过诱导早产肠道中TLR信号通路的成熟来防止对新定植细菌的高反应性;和（3）益生菌因子通过加速早熟肠道中TLR信号通路的成熟来预防NEC的发作。该项目的成功完成将为TLR信号通路的控制元件的个体发育以及类固醇和益生菌对其的调节提供新的基本信息。对类固醇和益生菌预防早产儿炎症作用的机制理解可用于设计有效的治疗策略来预防NEC的发生。这一点很重要，因为NEC是早产儿面临的重要公共卫生问题，占美国所有死亡人数的10%。

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.