Neonatal hyperbilirubinemia in a humanized UGT1 animal model

人源化 UGT1 动物模型中的新生儿高胆红素血症

基本信息

批准号：
8786086
负责人：
Robert H Tukey
金额：
$ 32.27万
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：
2012
资助国家：
美国
起止时间：
2012-03-15 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786086
关键词：
Acids Adult Animal Model Apoptosis Behavior Bile Acids Bile fluid Bilirubin Biological Birth Blood Brain Brain Injuries Catabolism Cells Cessation of life Child Clinical Coupled Data Deposition Development Diet Disease Drug Metabolic Detoxication Dystonia Encephalopathies Event Extrahepatic Fatty Acids Foundations Functional disorder Gastrointestinal tract structure Gene Expression Profile Genes Genetic Glucuronides Glucuronosyltransferase Heme Hepatic Homeostasis Human Hyperbilirubinemia Icterus Impairment Incidence Inflammation Intestines Irreversible Toxicity Kernicterus Knockout Mice Knowledge Laboratories Lead Limb structure Link Liver Metabolism Methods Molecular Movement Mus Muscle Mutation Neonatal Neonatal Jaundice Neuraxis Neurologic Dysfunctions Neurotransmitters Newborn Infant Normal tissue morphology Ophthalmoplegia Oxidative Stress Paralysed Pathway interactions Phenotype Play Premature Infant Process Proteins RNA Regulation Role Route Seizures Serum Serum Albumin Shock Steroids Technology Therapeutic Tissues Toxic effect Transgenes UDP-Glucuronosyltransferase 1A1 UGT1A1 gene Urine Water Wild Type Mouse Xenobiotics brain tissue human tissue knockout gene mouse model neonatal death neonate premature response

项目摘要

DESCRIPTION (provided by applicant): Human UDP-glucuronosyltransferase 1A1, which is part of 9-UGT1A proteins encoded by the UGT1 locus, plays a key role in many aspects of normal pathophysiology. Glucuronidation carried out by UGT1A1 is considered the rate limiting step in bilirubin elimination. Over 50% of newborn babies do not process the elimination of bilirubin adequately, due mostly to a lag in developmental expression of UGT1A1. Clinically and in selective genetic deficiencies, severe hyperbilirubinemia leads to bilurubin toxicity, which is classified as kernicterus or the depositing of bilirubin into the brain. Kernicterus most often leas to early neonatal death. To date, there is a paucity of data regarding the mechanisms leading to developmental expression of human UGT1A1 in neonatal children and the mechanisms underlying the onset of kernicterus. To better understand these processes, our laboratory has created humanized mouse models that express all 9-UGT1A genes encoded by the human UGT1 locus. We have determined that expression levels of the UGT1A genes as determined by RNA quantitation in humanized adult mice are concordant with the expression patterns of these genes as determined in human tissues. These observations indicate that normal tissue specific and humoral control of the UGT1 locus in mice is regulated in a fashion similar to what occurs in humans. Interestingly, humanized UGT1 mice develop neonatal hyperbilirubinemia, a condition that returns to normal when the mice are adults. This unique phenotype associated with humanized UGT1 mice will allow us to investigate the regulatory mechanisms associated with developmental control of the UGT1A1 gene and its impact on serum bilirubin. Our preliminary findings indicate that developmental control of serum bilirubin in humanized UGT1 mice is tightly linked to extrahepatic UGT1A1 activity, a new observation that will be exploited in examining the mechanisms leading to control of hyperbilirubinemia. In addition, the accumulation of extreme levels of serum bilirubin by 14 days after birth triggers the accumulation of bilirubin in brain tissue resulting in seizures and death in approximately 10% of the developing mice. The consistency linking hyperbilirubinemia to bilirubin induced seizures and brain toxicity provides us with an animal model to examine the association between developmental regulation of UGT1A1 with the cellular and molecular mechanisms leading to bilirubin induced brain toxicity. Overall, these approaches will allow us to explore in greater detail the pathophysiological, biological, and molecular mechanisms that control the developmental expression of UGT1A1 and its impact on normal bilirubin homeostasis and disease. This knowledge and information will serve as the foundation for examining new therapies and potential treatments to reduce the incidence of bilirubin induced toxicities in humans.

描述（由申请人提供）：人类UDP-葡萄糖基转移酶1A1，是由UGT1基因座编码的9-ugt1a蛋白的一部分，在正常病理生理学的许多方面都起着关键作用。 UGT1A1进行的葡萄糖醛酸化被认为是胆红素消除的速率限制步骤。超过50％的新生婴儿无法充分处理胆红素，这主要是由于UGT1A1发育表达的滞后。在临床和选择性遗传缺陷中，严重的高胆红素血症会导致胆红素毒性，该毒性被分类为核或胆红素沉积到大脑中。内核最常见于新生儿早期死亡。迄今为止，有关导致新生儿儿童中人类UGT1A1发育表达的机制以及核心发作的机制的数据很少。为了更好地了解这些过程，我们的实验室创建了人性化的小鼠模型，该模型表达了由人类UGT1基因座编码的所有9-ugt1a基因。我们已经确定，在人源化小鼠中通过RNA定量确定的UGT1A基因的表达水平与这些基因在人体组织中确定的表达模式一致。这些观察结果表明，小鼠中UGT1基因座的正常组织特异性和体液在以类似于人类发生的方式调节。有趣的是，人源化的UGT1小鼠会发展出新生儿高胆红素血症，这种病在成年小鼠时会恢复正常。与人源化的UGT1小鼠相关的这种独特的表型将使我们能够研究与UGT1A1基因发育控制相关的调节机制及其对血清胆红素的影响。我们的初步发现表明，人源化的UGT1小鼠中血清胆红素的发育控制与肝外ugt1a1活性密切相关，这是一种新的观察结果，在检查导致高胆红素血症控制的机制时会被利用。此外，出生后14天，血清胆红素的极端水平的积累会触发胆红素在脑组织中的积累，从而导致大约10％的发育中的小鼠癫痫发作和死亡。将高胆红素血症与胆红素引起的癫痫发作和脑毒性联系起来的一致性为我们提供了使用动物模型来检查UGT1A1的发育调控与导致胆红素诱导脑毒性的细胞和分子机制之间的关联。总体而言，这些方法将使我们能够更详细地探索病理生理，生物学和控制UGT1A1的发育表达及其对正常胆红素稳态和疾病的影响的分子机制。这些知识和信息将是检查新疗法和潜在疗法的基础，以降低胆红素引起的人类毒性的发生率。