Ah Receptor Anatomy: Implications for Dioxin Toxicity

描述（由申请人提供）：这是一份响应NIH通知编号no - od -09-058的申请，题为“NIH宣布竞争性修订申请的恢复法案资金可用性”。毒素、致病性感染（病毒和细菌）以及肝脏的物理损伤会导致肝组织的损失，从而引发恢复肝细胞群的再生反应。修复过程中的失调会导致肝功能衰竭或肝癌。芳烃受体（AhR）是一种配体激活的转录因子，在功能上与增殖过程有关。暴露于配体2,3,7,8-四氯二苯并-对二恶英（TCDD）后发生的持续AhR信号传导可诱导一系列毒性或适应性终点，包括组织损伤后肝脏再生失败。我们的长期目标是了解AhR如何通过调节细胞增殖来促进肝脏稳态，从而确定tcdd诱导的正常生物过程中断的分子基础。本应用的中心假设是，AhR诱导对氧磷酶1 （PON1）基因表达，以响应肝脏再生期间产生的氧化低密度脂蛋白（oxLDL）。这一假设是根据几项观察得出的。首先，有报道称pon1（一种在高密度脂蛋白中发现的抑制氧化低密度脂蛋白产生的酶）是AhR靶基因。其次，最近发表的研究发现，剪切应力诱导oxLDL的产生可以诱导AhR激活。第三，肝损伤引起的血流动力学改变导致oxLDL的形成。此外，根据我们的初步证据，我们提出PON1表达使用独特的AhR蛋白复合物结合新的非共识异种反应元件（NC-XRE）。本提案所述的研究将证实，在肝脏再生过程中，oxLDL诱导的PON1表达是nc - xre介导的AhR依赖过程，其中PON1表达主要通过调节oxLDL的形成来控制AhR活性。鉴于PON1在预防心血管疾病中所起的作用，以及现在被怀疑在肝脏稳态中所起的作用，AhR对其的调节直接将环境暴露与重大和普遍的人类健康问题联系起来。因此，对这些过程的机械理解是必不可少的。)

DESCRIPTION (provided by applicant): This is an application in response to the NIH Notice Number NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Application." Toxins, pathogenic infection (viral and bacterial), and physical injury to the liver results in a loss of hepatic tissue, triggering a regenerative response to restore liver cell mass. Dysregulation in the repair process can lead to liver failure or liver cancer. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor functionally identified with proliferative processes. Prolonged AhR signaling such as occurs following exposure to the ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces a range of toxic or adaptive endpoints including a failure of liver regeneration following tissue injury. Our long-term goal is to understand mechanistically how the AhR contributes to liver homeostasis by regulating cell proliferation, and thereby identify the molecular basis for TCDD-induced disruption of normal biological processes. The central hypothesis in this application states that the AhR induces paraoxonase 1 (PON1) gene expression in response to oxidized low-density lipoproteins (oxLDL) generated during periods of liver regeneration. The hypothesis is based on several observations. First, a report that PON1-an enzyme found in high-density lipoproteins responsible for inhibiting oxLDL production-is an AhR target gene. Second, the recently published finding that shear-stress induced production of oxLDL can induce AhR activation. Third, that hemodynamic changes triggered by liver injury lead to formation of oxLDL. Moreover, based on our preliminary evidence we propose that PON1 expression uses a unique AhR protein complex binding to a novel non-consensus xenobiotic response element (NC-XRE). The studies described in this proposal will establish that oxLDL- induced PON1 expression is a NC-XRE-mediated AhR-dependent process during liver regeneration, in which PON1 expression functions primarily to control AhR activity by regulating oxLDL formation. Given PON1's implicated role in protecting against cardiovascular disease, and now suspected role in liver homeostasis, its regulation by the AhR directly links environmental exposure concerns to significant and pervasive human health problems. Therefore, a mechanistic understanding of these processes is essential.) PUBLIC HEALTH RELEVANCE: Injury to the liver resulting in a loss of tissue triggers a repair process designed to restore liver mass, where inappropriate repair can lead to liver failure or liver cancer. The aryl hydrocarbon receptor (AhR) is a protein that plays a central role in liver repair in addition to being a sensor for environmental pollutants. Therefore, the AhR directly links environmental exposure concerns to significant and pervasive human health problems.)