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 新生儿严重高胆红素血症和坏死性小肠结肠炎是最常见的原因 全球新生儿发病率最高，这两种症状都与母乳有关。肠内 配方奶喂养是诱发早产儿NEC的直接生物标志物，而HBM具有保护作用 对NEC的指控。在新生儿中，HBM抑制UDP-葡萄糖醛酸基转移酶(UGT)1A1的表达，这是唯一的 能结合胆红素的转移酶，从而导致高胆红素血症。 表达人类UGT1A1基因的人源化UGT1(HUGT1)小鼠模拟在 人类与新生的hUGT1小鼠发生SNH。作为一种动物模型来研究 导致UGT1A1基因的调节，我们已经证明UGT1A1基因在肝脏中被抑制 在血清总胆红素(TSB)蓄积中起关键作用的组织。而大约10%的人 新生的hUGT1小鼠患上核脑病(KSD)，这是致命的，大多数新生儿 是健康的，有正常的生殖周期，并且是研究潜在的 将UGT1A1表达与SNH联系起来的机制。我们实验室的新发现证明 肠道UGT1A1表达的延迟受核受体转录的特异性控制 辅阻遏子蛋白，NCoR1。当NCoR1通过基因敲除实验变得不起作用时 在肠道中，新生儿TSB水平正常，肠道UGT1A1显著诱导，原因是 肠上皮细胞(IEC)成熟。新生hUGT1小鼠肠道UGT1A1的延迟是一种直接的 由于配方奶喂养会导致UGT1A1的显著诱导，因此母乳喂养可能会导致UGT1A1。HBM扮演着关键角色 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，但理解这一点至关重要，因为 胆红素是一种有效的抗氧化剂，可以对抗氧化应激引起的肠道炎症， 通向NEC。因此，我们努力的重点将决定互补的细胞机制是否与 SNH和NEC的发展。主要重点领域，根据现有出版物和 初步发现，微生物区系、TRL4信号、HBM寡糖和 新生儿IEC成熟，SNH和NEC的调控。概述了这些实验 预计将使人们更好地理解这些症状，并使用新的小鼠 模型和先进技术将使我们能够将出生后的早期生物事件联系起来 与SNH的发育控制有关，这些过程将与NEC的发病有关。因为 对于SNH或NEC的长期治疗，目前还没有有效的治疗干预措施 这项工作的目标和导致这些综合征的机制的解体将利用这一点 信息促进了有效治疗的发展。