Molecular targets in cholestasis caused by bile salt export pump deficiency

胆盐输出泵缺陷引起的胆汁淤积的分子靶点

基本信息

批准号：
9789255
负责人：
Chunyue Yin
金额：
$ 36.24万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789255
关键词：
ATP-Binding Cassette Transporters Accounting Adult Age Alternative Therapies Animal Model Animals Attenuated Autophagocytosis Bile Acids Bile fluid Child Cholestasis Cytoplasm Data Excretory function Exhibits Genes Genetic Goals Health Hepatocyte Heterozygote Human Impairment In Vitro Injury Knockout Mice Knowledge Life Liver Liver Failure Liver diseases Membrane Mission Modeling Molecular Molecular Target Mutation Neonatal Orthologous Gene Outcome P-Glycoprotein Patient-Focused Outcomes Patients Phenotype Primary carcinoma of the liver cells Progressive intrahepatic cholestasis Public Health Pump Research Severities Sirolimus Testing Trehalose United States National Institutes of Health Vesicle Zebrafish base bile salts cholestatic liver disease design disability early onset experimental study genome sequencing improved in vivo infancy innovation liver injury liver transplantation mTOR Inhibitor mutant new therapeutic target novel novel strategies novel therapeutics predictive marker premature restoration targeted treatment whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT In humans, mutations in the ABCB11 gene impair bile salt export pump (BSEP) function and cause progressive familial intrahepatic cholestasis type II (PFIC2), which is a fast-progressing and often-fatal liver disease in infancy. Liver transplantation remains as the only curable treatment for many PFIC2 patients. The main challenge for developing alternative therapy is that there is no known mechanism allowing restoration of bile excretion in the absence of BSEP. Our long-term goal is to discover molecular targets to treat cholestatic liver diseases. The overall objective for this application is to identify mechanisms that can be activated to restore bile excretion in the context of BSEP deficiency. Based on the preliminary data generated using the abcb11b mutant zebrafish, the central hypothesis is that alternative transporters can be prompted to excrete bile acids in BSEP-deficient hepatocytes. The rationale for the proposed research is that, finding the alternative bile salt transporter and delineating the molecular mechanisms triggering its bile excretion function will facilitate the designing of targeted therapies to treat cholestasis caused by BSEP deficiency. Identifying novel strategies to modulate bile secretion will also benefit the patients with other cholestatic liver diseases. The central hypothesis will be tested by the experiments proposed in three complementary specific aims: 1) Determine the alternative transporter that can be prompted to excrete bile acids in BSEP-deficient hepatocytes; 2) Define the cellular and molecular mechanisms that can be activated to restore bile excretion in BSEP-deficient hepatocytes; and 3) Identify genetic modifiers that restore bile excretion in BSEP-deficient hepatocytes. The first aim will test the hypothesis that recovering the localization of another ABC transporter MDR1 to the bile canaliculus allows it to assume bile excretion function in BSEP-deficient hepatocytes. The second aim will investigate whether augmentation of autophagy represents a novel mechanism to restore bile excretion in hepatocytes with BSEP deficiency. The third aim will utilize an unbiased whole-genome sequencing approach to identify genetic modifiers of BSEP-deficiency phenotype severity. The research proposed in this application is highly innovative, because it uses the zebrafish model that offers unique advantages for studying bile excretion, and abcb11b mutant zebrafish is the first animal model in which loss of BSEP results in severe perturbation of bile excretion as seen in patients with PFIC2. The proposed research is significant, because it is expected to reveal strategies to restore bile excretion in BSEP-deficient hepatocytes and uncover new therapeutic targets for treating cholestatic liver diseases.

项目概要/摘要在人类中，ABCB11 基因突变会损害胆汁盐输出泵 (BSEP) 功能并导致进行性家族性肝内胆汁淤积 II 型 (PFIC2)，这是一种进展快速且常常致命的肝脏疾病婴儿期患病。肝移植仍然是许多 PFIC2 患者唯一可治愈的治疗方法。开发替代疗法的主要挑战是没有已知的机制允许在没有 BSEP 的情况下恢复胆汁排泄。我们的长期目标是发现分子靶点治疗胆汁淤积性肝病。该应用程序的总体目标是确定可以在 BSEP 缺乏的情况下被激活以恢复胆汁排泄。根据初步数据使用 abcb11b 突变斑马鱼生成，中心假设是替代转运蛋白可以促使缺乏 BSEP 的肝细胞分泌胆汁酸。拟议研究的理由是寻找替代的胆汁盐转运蛋白并描述触发其胆汁的分子机制排泄功能将有助于设计治疗 BSEP 引起的胆汁淤积的靶向疗法不足。确定调节胆汁分泌的新策略也将使患有其他疾病的患者受益胆汁淤积性肝病。中心假设将通过三个实验中提出的实验进行检验互补的具体目标：1）确定可以促进胆汁排泄的替代转运蛋白 BSEP 缺陷肝细胞中的酸； 2）定义可激活的细胞和分子机制恢复 BSEP 缺陷肝细胞的胆汁排泄； 3) 识别恢复胆汁的基因修饰剂 BSEP 缺陷肝细胞中的排泄。第一个目标将检验以下假设：恢复另一个 ABC 转运蛋白 MDR1 定位于胆小管，使其能够排泄胆汁 BSEP 缺陷肝细胞中的功能。第二个目标将调查是否增强自噬代表了一种恢复 BSEP 缺乏的肝细胞胆汁排泄的新机制。第三个目标将利用公正的全基因组测序方法来识别基因修饰因子 BSEP 缺乏表型严重程度。本申请提出的研究具有高度创新性，因为它使用斑马鱼模型，为研究胆汁排泄提供了独特的优势，而 abcb11b 突变斑马鱼是第一个 BSEP 缺失导致胆汁严重紊乱的动物模型 PFIC2 患者中观察到的排泄。拟议的研究意义重大，因为预计揭示恢复 BSEP 缺陷肝细胞胆汁排泄的策略并发现新的治疗方法治疗胆汁淤积性肝病的目标。