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.

抽象的 严重的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 全世界新生儿的发病率都很高，这两种症状都与母乳 (HBM) 有关。肠内 配方奶喂养是早产新生儿诱导 NEC 的直接生物标志物，而 HBM 可以保护 反对NEC。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 转移酶能够结合胆红素，从而导致高胆红素血症的发生。 表达人类 UGT1A1 基因的人源化 UGT1 (hUGT1) 小鼠模拟了在 人类与新生 hUGT1 小鼠发生 SNH。作为研究机制的动物模型 导致 UGT1A1 基因的调节，我们已经证明 UGT1A1 基因在肝脏中受到抑制 组织，在血清总胆红素 (TSB) 积累中起关键作用。虽然大约 10% 新生 hUGT1 小鼠会出现核黄疸谱系障碍 (KSD)，这种疾病是致命的，大多数新生儿 是健康的，有正常的生殖周期，并且是研究潜在问题的优秀模型 将 UGT1A1 表达与 SNH 联系起来的机制。我们实验室的新发现表明 肠道UGT1A1表达的延迟是由核受体转录特异性控制的 辅阻遏蛋白，NCoR1。当 NCoR1 通过基因敲除实验变得失去功能时 在肠道中，新生儿 TSB 水平正常，并且肠道 UGT1A1 被显着诱导，这是由于 肠上皮细胞（IEC）成熟。新生 hUGT1 小鼠肠道 UGT1A1 的延迟是直接原因 母乳的结果，因为配方奶喂养会导致 UGT1A1 的显着诱导。 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胆红素的影响，促进 SNH 的发展 NEC。因此，我们假设导致 SNH 的潜在机制也与潜在的 调节 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，我们努力的重点将确定互补的细胞机制是否与 SNH和NEC的发展。主要重点领域，基于当前出版物和 初步发现将微生物区系、TRL4 信号传导、HBM 寡糖和 新生儿IEC的成熟，受SNH和NEC的控制和调节。实验概述 预计将通过使用新型小鼠来更好地了解这些综合征 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 通过与 NEC 发生相关的相同过程来控制 SNH 的发育。因为 不存在有效的治疗干预措施来治疗 SNH 或 NEC，长期来看 这项工作的目标以及揭示导致这些综合症的机制将是利用这一点 信息以改善有效疗法的开发。