The Perinatal Pharmacology of the Nuclear Receptor

核受体的围产期药理学

基本信息

批准号：
8628853
负责人：
Wen Xie
金额：
$ 30.76万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628853
关键词：
Acids Agonist Bile Acid Biosynthesis Pathway Bile Acids Biliary Biological Availability CYP7A1 gene Childhood Chronic Clinical Data Development Disease Embryo Fibroblast Growth Factor Funding Genes Genetic Goals Hepatic Hepatobiliary Hepatotoxicity Human Hypersensitivity Inflammation Inflammation Mediators Intestines Lactation Liver Malnutrition Milk Mus Neonatal Newborn Infant Nuclear Receptors Nurses Perinatal Pharmaceutical Preparations Pharmacology Proteins Receptor Activation Research Personnel Response Elements Role Testing Tetracyclines Therapeutic Toxic effect Transgenes Transgenic Mice Transgenic Organisms United States National Institutes of Health Vitamins Wild Type Mouse absorption base dietary supplements farnesoid X-activated receptor feeding knock-down liver function mature animal meetings novel postnatal promoter public health relevance pup receptor research study response small hairpin RNA therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): This is the resubmission of R01 HD073070, which was submitted in response to PAR-11-057. Our goal is to understand the perinatal liver function of the nuclear receptor farnesoid X receptor (FXR), especially the hepatic consequence of FXR activation during perinatal development. Recent studies have suggested multiple therapeutic benefits of FXR activation and as a result, FXR has been intensively pursued as a therapeutic target. The majority of the previous conclusions on the function of FXR have relied on the use of adult animals, whereas little is known about the function of FXR during the perinatal development. Activation of FXR suppresses bile acid synthesis through the transcriptional suppression of CYP7A1. It is believed that the perinatal livers are particularly sensitive to a decreased bile acid pool size because of a lower basal expression of CYP7A1, as well as the insufficient enterohepatic bile acid recirculation in the early postnatal period. Bile acids are clinical drugs that have been used to treat hepatobiliary diseases including certain pediatric disorders. There are also ample opportunities for perinatal activation of FXR as a result of maternal use of bile acid drugs and other non-bile acid FXR-activating agents. As such, it is imperative to understand the perinatal pharmacology of FXR. Our preliminary results show that: 1) Perinatal activation of FXR in transgenic mice resulted in hepatotoxicity, partial lethality, an signs of inflammation; 2) The perinatal toxicity of the FXR transgene was associated with a decreased biliary secretion of bile acids, likely due to the suppression of Cyp7a1; 3) Perinatal dietary supplement of bile acids and/or vitamins relived the hepatotoxicity and partial lethality o the transgenic pups; 4) There was a material effect on the survival of the transgenic mice, in which the transgenic pups nursed by transgenic dams had a worse survival than those nursed by control dams; 5) The perinatal toxicity of FXR was associated with the activation of the fibroblast growth factor-inducible immediate-early response protein 14 (Fn14), a gene highly expressed in the neonatal liver and implicated in inflammation. A putative FXR response element has been identified in the Fn14 gene promoter, suggesting Fn14 as a transcriptional target of FXR; and 6) we have successfully synthesized 6?-ECDCA, a potent FXR agonist with a favorable bioavailability. Based on our preliminary data, we hypothesize that FXR has a previously unrecognized role during perinatal development. Specifically, we hypothesize that activation of FXR might be toxic to the liver during perinatal development due to 1) the inhibition of bile acid synthesis; 2) a deficiency in intestinal vitamin absorption; 3) a perinatal hypersensitivity to decreased bile acid pool size; and 4) the "toxic milk" as a result of maternal FXR activation. Moreover, the perinatal toxicity of FXR might have been contributed to by the activation of Fn14, a novel transcriptional target of FXR. We propose four specific aims to test our hypotheses: (1) To determine whether a genetic activation of FXR during perinatal development is toxic to the liver, and whether the perinatal toxicity will be relieved by the dietay supplement of bile acids and/or vitamins; (2) To determine whether a pharmacological activation of FXR during perinatal development is toxic to the liver, and whether the pharmacological effect is FXR- dependent; (3) To determine the maternal effect of FXR activation on perinatal toxicity; and (4) To determine whether Fn14 is a transcriptional target of FXR and whether Fn14 is necessary for the perinatal toxicity of FXR. To our knowledge, this study represents the first attempt to systematically evaluate the perinatal pharmacology of FXR. Results from this study will increase our understanding of the perinatal function of FXR, which will offer better guidance in harnessing the therapeutic benefit of FXR. *This applicant agrees and has requested funds to participate in the annual NIH-sponsored two-day meetings focusing on Developmental Pharmacology in Bethesda, MD. This applicant also agrees to cooperate with other investigators.

描述（由申请人提供）：这是R01 HD073070的重新提交，该重新响应于Par-11-057。我们的目标是了解核受体Farnesoid X受体（FXR）的围产期肝功能，尤其是在围产期发育过程中FXR激活的肝后果。最近的研究表明，FXR激活的多种治疗益处，因此，FXR被强烈追求作为治疗靶点。先前关于FXR功能的大多数结论都依赖于成年动物的使用，而对FXR在围产期发育过程中的功能知之甚少。 FXR的激活通过CYP7A1的转录抑制抑制胆汁酸的合成。据认为，由于CYP7A1的基础表达较低，并且在产后早期，围产期肝脏对胆汁酸池尺寸的降低特别敏感。胆汁酸是用于治疗包括某些儿科疾病在内的肝胆管疾病的临床药物。由于母亲使用胆汁酸药物和其他非胆汁FXR激活剂，也有足够的FXR围产期激活FXR的机会。因此，必须了解FXR的围产期药理学。我们的初步结果表明：1）转基因小鼠中FXR的围产期激活导致肝毒性，部分致死性，炎症的迹象； 2）FXR转基因的围产期毒性与胆汁酸的胆汁分泌降低有关，这可能是由于CYP7A1的抑制作用。 3）胆汁酸和/或维生素的围产期饮食补充剂重现了转基因幼犬的肝毒性和部分致死性； 4）对转基因小鼠的存活产生了物质作用，其中转基因大坝护理的转基因幼崽的生存率比对照大坝护理的转基因较差。 5）FXR的围产期毒性与成纤维细胞生长因子诱导的即时反应蛋白14（FN14）的激活有关，该基因在新生儿肝脏中高度表达并与炎症有关。在FN14基因启动子中已经确定了推定的FXR响应元件，这表明FN14是FXR的转录靶标。 6）我们成功合成了6？-ECDCA，这是一种有效的生物利用度的有效FXR激动剂。根据我们的初步数据，我们假设FXR在围产期发育过程中具有先前未识别的作用。具体而言，我们假设FXR的激活在围产期发育过程中可能对肝脏有毒1）胆汁酸合成； 2）缺乏肠道维生素的吸收； 3）对胆汁酸池尺寸降低的围产期超敏反应； 4）由于母体FXR激活而导致的“有毒牛奶”。此外，FXR的围产期毒性可能是由FN14的激活（FXR的新转录靶标的激活）促成的。我们提出了四个特定的目的来检验我们的假设：（1）确定在围产期发育过程中FXR的遗传激活是否对肝脏有毒，以及围产期毒性是否会因胆汁酸和/或维生素的饮食补充剂而缓解。（2）确定围产期发育过程中FXR的药理激活是否对肝脏有毒，以及药理学作用是否依赖于FXR；（3）确定FXR激活对围产期毒性的产妇影响；（4）确定FN14是否是FXR的转录靶标，以及FN14是否对于FXR的围产期毒性是必需的。据我们所知，这项研究是系统评估FXR围产期药理学的首次尝试。这项研究的结果将增加我们对FXR的围产期功能的理解，这将为利用FXR的治疗益处提供更好的指导。 *该申请人同意，并已要求资金参加，参加的NIH年度赞助的为期两天的会议，重点是马里兰州贝塞斯达（Bethesda）的发育药理学。该申请人还同意与其他调查人员合作。