Neonatal hyperbilirubinemia in a humanized UGT1 animal model

描述（由申请人提供）：人udp -葡萄糖醛酸糖基转移酶1A1是UGT1位点编码的9-UGT1A蛋白的一部分，在正常病理生理的许多方面起着关键作用。由UGT1A1进行的糖醛酸化被认为是胆红素消除的限速步骤。超过50%的新生儿不能充分处理胆红素的消除，主要是由于UGT1A1的发育表达滞后。在临床上和选择性遗传缺陷中，严重的高胆红素血症导致胆红素毒性，这被归类为核黄疸或胆红素沉积到大脑中。核黄疸最常导致新生儿早期死亡。迄今为止，关于导致新生儿UGT1A1发育表达的机制和核黄疸发病的潜在机制的数据缺乏。为了更好地理解这些过程，我们的实验室创建了表达人类UGT1位点编码的所有9-UGT1A基因的人源化小鼠模型。我们已经确定，通过RNA定量测定的UGT1A基因在人源化成年小鼠中的表达水平与这些基因在人体组织中的表达模式是一致的。这些观察结果表明，小鼠UGT1基因座的正常组织特异性和体液控制以类似于人类的方式受到调节。有趣的是，人源化UGT1小鼠会出现新生儿高胆红素血症，当小鼠成年后，这种情况会恢复正常。这种与人源化UGT1小鼠相关的独特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。我们的初步研究结果表明，人源化UGT1小鼠血清胆红素的发育控制与肝外UGT1A1活性密切相关，这一新的观察结果将被用于研究导致高胆红素血症控制的机制。此外，在出生后14天，血清胆红素的极端水平的积累引发了脑组织胆红素的积累，导致大约10%的发育中的小鼠癫痫发作和死亡。高胆红素血症与胆红素引起的癫痫发作和脑毒性之间的一致性为我们提供了证据

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.