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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.

项目总结/文摘