Ileal Bile Acid Transporter Metabolism and Regulation

项目概要（来自母公司R 01 DK 047987赠款）： 总的目的是提高我们对根尖钠依赖性胆汁 酸转运蛋白（ASBT）和有机溶质转运蛋白α-β（OSTab）在肠梗阻发病机制中的作用 和肝胆疾病。总的来说，我们的研究结果强烈支持这一概念，除了其 ASBT-OSTab是维持胆汁酸（BA）稳态的重要作用，具有保护回肠上皮的功能 抗BA诱导的损伤。此外，ASBT-OSTab的保护作用的概念可能是 通过我们鉴定出的一种新的胆汁酸转运蛋白， 两例先天性腹泻患儿OSTb（SLC 51 B）功能失调突变的研究， 肝脏疾病然而，尽管取得了进展，但BA和毒性胆汁在人类疾病发病机制中的作用仍有待进一步研究。 并且高度有效的治疗干预的机会仍然难以捉摸。根据申请人的 最近发表的研究和强有力的初步数据，提出了三个具体目标，询问ASBT- OSTab在疾病发病机制中的作用以及基于BA的新疗法的作用机制。 具体目标1旨在阐明与以下疾病相关的回肠损伤的分子机制 OSTa失活。这将通过检查BA和活性氧的作用来实现 (ROS)在Osta基因敲除小鼠的肠损伤和恢复反应中的作用，以及Nox 1和Nrf 2在 这个过程。具体目标2旨在阐明ASBT在BA胆肝分流中的作用 以及治疗和细胞毒性BA的作用。这将通过审查以下要求来实现： ASBT在BA胆肝分流中的应用，富碳酸氢盐高胆固醇血症对ASBT的要求 治疗性BA（如UDCA和norUDCA）诱导的胆汁性ASBT，以及胆汁性ASBT在梗阻性结肠炎模型中的作用 胆汁淤积具体目标3旨在检验OSTab功能可保护人类的假设 肝细胞和/或胆管细胞免受BA诱导损伤。这将使用肝细胞和 胆管细胞体外模型。这些创新的研究将产生新的见解的途径， BA诱导的损伤和BA的胆肝分流在健康和疾病中的作用，目的是将其转化为 新的预防措施和治疗方法。

PROJECT SUMMARY (from parent R01 DK047987 grant): The overall objective is to advance our understanding of the relationship of the Apical Sodium-dependent bile acid transporter (ASBT) and Organic Solute Transporter alpha-beta (OSTab) to the pathogenesis of intestinal and hepatobiliary disease. Collectively, our findings strongly support the concept that in addition to its essential role in maintaining bile acid (BA) homeostasis, ASBT-OSTab functions to protect the ileal epithelium against BA-induced injury. Moreover, the concept of a protective role for ASBT-OSTab can potentially be extended to other BA-transporting epithelium and the cholehepatic shunt pathway by our identification of a dysfunctional mutation in OSTb (SLC51B) in two pediatric patients with congenital diarrhea and features of liver disease. However, despite progress, the role of BAs and toxic bile in the pathogenesis of human disease and the opportunities for highly effective therapeutic intervention remain elusive. Guided by the applicants’ recently published studies and strong preliminary data, three specific aims are proposed to interrogate ASBT- OSTab’s role in the pathogenesis of disease and the mechanism of action of new BA-based therapies. Specific Aim 1 is designed to elucidate the molecular mechanisms underlying the ileal injury associated with inactivation of OSTa. This will be accomplished by examining the roles for BAs and reactive oxygen species (ROS) in the intestinal injury and restitution response in Osta null mice, and the roles of the Nox1 and Nrf2 in that process. Specific Aim 2 is designed to elucidate the role of the ASBT in the cholehepatic shunting of BAs and the actions of therapeutic and cytotoxic BAs. This will be accomplished by examining the requirement for ASBT in cholehepatic shunting of BAs, the requirement for ASBT in the bicarbonate-rich hypercholeresis induced by therapeutic BAs such as UDCA and norUDCA, and the role of biliary ASBT in models of obstructive cholestasis. Specific Aim 3 is designed to test the hypothesis that OSTab functions to protect human hepatocytes and/or cholangiocytes from BA-induced injury. This will be accomplished using hepatocyte and cholangiocyte in vitro models. These innovative studies will yield novel insights to the the pathways underlying BA-induced injury and role of cholehepatic shunting of BAs in health and disease, with the goal of translating those insights into new preventive measures and treatments.