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.
This the re-submission of a proposal submitted in response to PAR-11-057 Developmental Pharmacology (R01). The farnesoid X receptor (FXR) is a nuclear receptor highly expressed in the liver and intestine. Previous studies have suggested multiple therapeutic benefits of FXR. However, 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 specific function of FXR during the perinatal development. The goal of this proposal is to understand the perinatal liver function of FXR, especially the hepatic consequence of FXR activation during perinatal development. To our knowledge, this study represents the first attempt to systematically evaluate the perinatal function 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 benefits of FXR.
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