Novel regulatory events that control expression of the UGT1A1 gene

控制 UGT1A1 基因表达的新调控事件

基本信息

批准号：
10061607
负责人：
Robert H Tukey
金额：
$ 29.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10061607
关键词：
Acetylgalactosamine Acute Adult Animal Model Antioxidants Aryl Hydrocarbon Receptor Behavior Benign Bilirubin Blood Child Chronic Chronic Brain Damage Complex Congenital cerebellar hypoplasia Coupled Cytolysis Defect Development Drops Epigenetic Process Erythrocytes Event Exhibits Future Gastrointestinal tract structure Gene Expression Generations Genes Genetic Predisposition to Disease Genetic Transcription Glucuronosyltransferase Hepatic Human Hyperbilirubinemia Intestines Isothiocyanates Kernicterus Knock-out LXRalpha protein Laboratories Lead Ligand Binding Ligands Link Liver Mediator of activation protein Metabolism Molecular Morbidity - disease rate Mus NCOR1 gene Neonatal Neonatal Jaundice Nuclear Nuclear Receptors Oral Administration Oxidative Stress PPAR alpha Pathway interactions Phenethyl Isothiocyanate Phenobarbital Physiological Play Pregnenolone Premature Birth Property Proteins Publishing Reactive Oxygen Species Receptor Activation Regulation Repression Repressor Proteins Response Elements Risk Role Seizures Serum Small Interfering RNA Thyroid Hormone Receptor Thyroid Hormones Tissues Tretinoin UDP-Glucuronosyltransferase 1A1 UGT1A1 gene Xenobiotics autism spectrum disorder base biological adaptation to stress constitutive androstane receptor derepression dietary supplements experimental study gene repression genetic corepressor human tissue knock-down low and middle-income countries member mortality myelination neonatal human neonatal mice neonatal period neurotoxicity novel prevent receptor receptor function response therapeutically effective

项目摘要

The human UDP-glucuronosyltransferase 1A1 (UGT1A1) gene is regulated at the transcriptional level by a host of xenobiotic nuclear receptors (XNRs), including PXR, CAR, LXRα/β, PPARα in addition to the Ah receptor and the antioxidant response factor Nrf2. Exposure of specific ligands that targets any of these receptors will lead to induction of the UGT1A1 gene. UGT1A1 is expressed in many tissues, but predominantly in the liver and gastrointestinal (GI) tract in adults. In addition, the UGT1A1 gene is developmentally regulated, with greatly reduced expression in the liver and GI tract during neonatal development. Reduced expression of UGT1A1 during development plays an important physiological role because UGT1A1 is the sole glucuronosyltransferase responsible for the metabolism of serum bilirubin. During neonatal development, reduced UGT1A1 expression results in a build-up of serum bilirubin that is presented as either moderate or severe hyperbilirubinemia. While usually benign, severe neonatal hyperbilirubinemia (SNH) can lead to acute and chronic encephalopathy, abnormal behavior, opisthotonus, seizures, cerebellar hypoplasia, with potential linkages to autism spectrum disorders. Thus, we hypothesize that in those children that are at heightened risk for bilirubin induced neurotoxicity, controlling or accelerating the metabolism of bilirubin and reducing total serum bilirubin (TSB) levels would prevent neurotoxicity. We have recently generated humanized UGT1 (hUGT1) mice where the murine Ugt1 locus was replaced with the human UGT1 locus, including the human UGT1A1 gene. The human UGT1A1 gene is regulated in a tissue specific and developmental fashion that is concordant with its expression in human tissues. Importantly, hUGT1 mice develop SNH during the neonatal stage, providing us with a unique animal model to examine the regulatory properties of the UGT1A1 gene. We have recently established that SNH in hUGT1 mice can lead to seizures, cerebellar hypoplasia, with significant myelination defects, all of which can be reversed by inducing either liver or GI tract UGT1A1 gene expression. With this background, three significant discoveries, all identified with in the last 1-2 years and linking regulation of the UGT1A1 gene to SNH will be examined in this proposal. First, the liver UGT1A1 gene is actively repressed during the neonatal period by the corepressor protein SMRT (silencing mediatory of retinoic acid and thyroid hormone receptor). Second, oral administration of isothiocyanates to neonatal hUGT1 mice, which are known to induce oxidative stress, dramatically induce liver UGT1A1 gene expression by activating liver CAR. Third, regulation of intestinal UGT1A1 expression during development is controlled by the corepressor protein NCoR1 (nuclear repressor corepressor). We have linked repression of intestinal UGT1A1 gene expression by NCoR1 with IKKβ activity and oxidative stress. The regulatory events that we have outlined, each of which can reduce the risk of SNH, will be examined to unravel these novel mechanisms leading to expression of the human UGT1A1 gene.

人UDP-葡萄糖基转移酶1A1（UGT1A1）基因在转录水平上受到宿主的调节异生物核受体（XNR），包括PXR，CAR，LXRα/β，PPARα，除了AH受体和抗氧化剂反应因子NRF2。靶向这些受体中任何一个的特定配体的暴露将导致诱导UGT1A1基因。 UGT1A1在许多组织中表达，但主要在肝脏中，成人的胃肠道（GI）。此外，开发了UGT1A1基因，并具有很大的调节新生儿发育过程中肝脏和胃肠道的表达降低。 UGT1A1的表达降低在开发过程中起着重要的身体作用，因为UGT1A1是唯一的谷氨酸转移酶负责血清胆红素的代谢。在新生儿发育期间，UGT1A1表达降低导致血清胆红素的积累，该血清胆红素被呈现为中度或严重的高胆红素血症。尽管通常，严重的新生儿高胆红素血症（SNH）会导致急性和慢性脑病，异常行为，蛋白石，癫痫发作，小脑发育不全，潜在与自闭症谱系联系疾病。这是我们假设，在那些诱发胆红素风险较高的孩子中神经毒性，控制或加速胆红素的代谢并减少总血清胆红素（TSB）水平将防止神经毒性。我们最近产生了人源化的UGT1（HUGT1）小鼠鼠UGT1基因座被包括人类UGT1A1基因在内的人类UGT1基因座取代。人类 UGT1A1基因受组织特异性和发育方式的调节，与其表达一致在人体组织中。重要的是，Hugt1小鼠在新生儿阶段发展了SNH，为我们提供了独特的动物模型检查UGT1A1基因的调节特性。我们最近确定了SNH 在Hugt1小鼠中，小脑发育不全，有明显的髓鞘缺陷，所有这些都可以通过诱导肝或胃肠道UGT1A1基因表达来逆转。在这个背景下，三个重要发现，在过去的1 - 2年中都确定了所有发现，并将UGT1A1基因的调节与SNH联系起来在此提案中进行了检查。首先，肝UGT1A1基因在新生儿期间积极反映 Corepressor蛋白SMRT（视黄酸和甲状腺激素受体的沉默介导）。第二，口头给予新生儿Hugt1小鼠的异硫氰酸盐，已知会诱导氧化应激，通过激活肝CAR来动态诱导肝UGT1A1基因表达。第三，肠道调节开发过程中的UGT1A1表达由Corepressor蛋白NCOR1（核复制器）控制 CorePressor）。我们已经通过NCOR1与IKKβ活性和氧化应激。我们概述的监管事件（每种事件都可以降低SNH的风险）将是检查以揭示这些新的机制，从而导致人类UGT1A1基因的表达。