Severe neonatal hyperbilirubinemia (SNH) and the expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) play key roles in the development of necrotizing enterocolitis (NEC)

严重新生儿高胆红素血症 (SNH) 和 UDP-葡萄糖醛酸基转移酶 1A1 (UGT1A1) 的表达在坏死性小肠结肠炎 (NEC) 的发生中起关键作用

• 批准号: 10713549
• 负责人: Robert H Tukey
• 金额: $ 64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713549
• 关键词: Acceleration; Acids; Acute; Affect; Age; Animal Model; Antioxidants; Area; Ataxia; Athetosis; Bilirubin; Biological; Biological Markers; Birth; Breast Feeding; Catabolism; Cell Lineage; Cell Maturation; Central Nervous System; Cerebral Palsy; Cessation of life; Clinical; Data; Defect; Development; Developmental Delay Disorders; Disease; Dystonia; Enteral; Event; Fatality rate; Food; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Heme; Human; Human Milk; Hyperbilirubinemia; Individual; Inflammatory; Intention; Intestines; Kernicterus; Knock-out; Knockout Mice; Laboratories; Link; Lipopolysaccharides; Liver; Metabolism; Modeling; Morbidity - disease rate; Movement Disorders; Mucous body substance; Mus; Muscle hypotonia; NCOR1 gene; Necrotizing Enterocolitis; Neonatal; Neonatal Jaundice; Newborn Infant; Nuclear Receptors; Nutrient; Oligosaccharides; Oxidative Stress Induction; Pathway interactions; Pattern; Pharmaceutical Preparations; Play; Process; Production; Property; Proteins; Publications; Regulation; Repression; Research; Risk; Role; Serum; Signal Transduction; Source; Symptoms; Syndrome; TLR4 gene; Technology; Term Birth; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Transferase; UDP-Glucuronosyltransferase 1A1; UGT1A1 gene; Work; combat; constitutive expression; effective therapy; experimental study; feeding; genetic corepressor; gut inflammation; gut microbiota; hearing impairment; improved; intestinal barrier; intestinal epithelium; mammary; microbiota; mouse model; neonatal mice; neonatal period; neonate; novel; nursing mothers; oculomotor; premature; preterm newborn; receptor; reproductive; therapeutic target; therapeutically effective

ABSTRACT Severe neonatal hyperbilirubinemia (SNH) and necrotizing enterocolitis (NEC) are the most common causes of morbidity in newborns worldwide, with both symptoms being linked to human breast milk (HBM). Enteral formula feeding is a direct biomarker for the induction of NEC in preterm newborns, while HBM protects against NEC. In newborns, HBM suppresses UDP-glucuronosyltransferase (UGT) 1A1 expression, the only transferase capable of conjugating bilirubin, thus contributing to the development of hyperbilirubinemia. Humanized UGT1 (hUGT1) mice that express the human UGT1A1 gene mimic what is observed in humans with neonatal hUGT1 mice developing SNH. As an animal model to examine the mechanisms that lead to regulation of the UGT1A1 gene, we have documented that the UGT1A1 gene is repressed in liver tissue, which plays a key role in total serum bilirubin (TSB) accumulation. While approximately 10% of the neonatal hUGT1 mice develop Kernicterus Spectrum Disorder (KSD), which is lethal, most of the newborns are healthy, have normal reproductive cycles, and represent an excellent model to study the underlying mechanisms linking UGT1A1 expression to SNH. New findings from our laboratory have demonstrated that the delay in intestinal UGT1A1 expression is controlled specifically by the nuclear receptor transcriptional corepressor protein, NCoR1. When NCoR1 is rendered non-functional through genetic knockout experiments in the intestines, neonatal TSB levels are normal and intestinal UGT1A1 is dramatically induced, resulting from intestinal epithelial cell (IEC) maturation. The delay in intestinal UGT1A1 in neonatal hUGT1 mice is a direct result of breast milk, since formula feeding leads to significant induction of UGT1A1. HBM plays a key role in the development of SNH by blocking bilirubin metabolism while simultaneously protecting newborns against NEC. Thus, we hypothesize that the underlying mechanisms leading to SNH are also linked to the underlying mechanisms that regulate NEC. This may not be a coincidence but crucially important to understand, since bilirubin is a potent antioxidant that could combat oxidative stress induced intestinal inflammation, which leads to NEC. Thus, the focus of our efforts will determine if complimentary cellular mechanisms are tied to the development of both SNH and NEC. The major focus areas, based upon current publications and preliminary findings, will be to tie the role of microflora, TRL4 signaling, HBM oligosaccharides, and neonatal IEC maturation, with the control and regulation of SNH and NEC. The experiments outlined are anticipated to lead to a greater understanding of these syndromes, made available using novel mouse models and advanced technology that will allow us to connect the early biological events after birth leading to the developmental control of SNH with those same processes that will be tied to the onset of NEC. Because there does not exist effective therapeutic interventions for the treatment of either SNH or NEC, the long-term goal of this work and the unraveling of the mechanisms leading to these syndromes will be to use this information to improve the development of effective therapy.

摘要 严重新生儿高胆红素血症（SNH）和坏死性小肠结肠炎（NEC）是最常见的原因 这两种症状都与人类母乳有关（HBM）。肠内 配方奶喂养是早产儿NEC诱导的直接生物标志物，而HBM保护 反对NEC。在新生儿中，HBM抑制UDP-葡萄糖醛酸转移酶（UGT）1A 1的表达， 能够结合胆红素的转移酶，从而促进高胆红素血症的发展。 表达人UGT 1A 1基因的人源化UGT 1（hUGT 1）小鼠模拟了在 人与新生hUGT 1小鼠发生SNH。作为一个动物模型来研究 导致UGT 1A 1基因的调节，我们已经证明UGT 1A 1基因在肝脏中被抑制， 组织，其在总血清胆红素（TSB）积累中起关键作用。虽然大约10%的 新生的hUGT 1小鼠发生致命的核黄疸谱系障碍（KSD），大多数新生小鼠 是健康的，有正常的生殖周期，并代表了一个很好的模型，研究潜在的 UGT 1A 1表达与SNH相关的机制。我们实验室的新发现表明， 肠UGT 1A 1表达的延迟是由核受体转录因子特异性控制的， 辅阻遏蛋白NCoR 1。当通过基因敲除实验使NCoR 1失去功能时 在肠道中，新生儿TSB水平是正常的，肠道UGT 1A 1是显着诱导，导致 肠上皮细胞（IEC）成熟。新生hUGT 1小鼠肠道UGT 1A 1的延迟是一个直接的 这是母乳喂养的结果，因为配方奶粉喂养导致UGT 1A 1的显著诱导。HBM发挥关键作用 通过阻断胆红素代谢，同时保护新生儿免受 NEC。因此，我们假设导致SNH的潜在机制也与潜在的 监管NEC的机制。这可能不是巧合，但理解起来至关重要，因为 胆红素是一种有效的抗氧化剂，可以对抗氧化应激诱导的肠道炎症， 导致NEC。因此，我们努力的重点将确定互补的细胞机制是否与 SNH和NEC的发展。主要重点领域，根据目前的出版物和 初步研究结果，将是配合作用的微生物，TRL 4信号，HBM寡糖， 新生儿IEC成熟，SNH和NEC的控制和调节。概述的实验 预计将导致更好地了解这些综合征，使用新的小鼠 模型和先进的技术，将使我们能够连接出生后的早期生物事件， SNH的发育控制与NEC的发病有关。因为 对于SNH或NEC的治疗，不存在有效的治疗干预， 这项工作的目标和解开导致这些综合征的机制将是利用这一点， 信息，以改善有效治疗的发展。