Signaling Pathways Influencing Liver Disease Phenotype in Antitrypsin Deficiency

影响抗胰蛋白酶缺乏症肝病表型的信号通路

基本信息

批准号：
9251285
负责人：
David H Perlmutter
金额：
$ 45.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251285
关键词：
1-Phosphatidylinositol 3-Kinase Adult Affect Autophagocytosis Betamethasone Biochemical Biological Models Breeding Caenorhabditis elegans Carbamazepine Cell Line Cells Degradation Pathway Disease Endoplasmic Reticulum Engineering FDA approved G-Protein Signaling Pathway GTP-Binding Proteins Genetic Genetic Engineering Grant Hepatic Hepatocarcinogenesis Hepatocyte Homozygote Insulin Insulin Receptor Insulin Signaling Pathway Investigation Lead Life Liver Liver Fibrosis Liver diseases Mammalian Cell Metformin Modeling Molecular Genetics Mus Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Play Point Mutation Polymers Post-Translational Protein Processing Primary carcinoma of the liver cells Process Proteins Quality Control Research Reserpine Role Signal Pathway Signal Transduction Signaling Protein Specific qualifier value Subgroup System TNFRSF5 gene Variant Work age related base design disease phenotype drug discovery early childhood gain of function individual patient induced pluripotent stem cell inducible gene expression infancy insulin signaling liver injury mouse model multicatalytic endopeptidase complex mutant novel novel therapeutics polymerization prevent protein degradation proteostasis proteotoxicity public health relevance secretory protein theories

项目摘要

DESCRIPTION (provided by applicant): In the classical form of α1antitrypsin deficiency (ATD) a point mutation leads to misfolding of a hepatic secretory protein and the variant, 1antitrypsin Z (ATZ), accumulates in the ER of liver cells as polymers and aggregates. Liver fibrosis and hepatocellular carcinoma develops in a subgroup of affected homozygotes by a gain-of-function 'proteotoxic' mechanism. There is wide variability in the hepatic phenotype with ~10% affected in infancy/early childhood and another subgroup that develop liver disease in the 6th-7th decade of life by an apparent age-dependent process. The central hypothesis of our research has 3 components: 1) variability in hepatic phenotype is determined by genetic and environmental modifiers; 2) the targets of these modifiers are the quality control mechanisms of the ER, part of the cell's proteostasis regulatory network; 3) the 2 major types of protestasis mechanisms are protein degradation pathways, such as the proteasome and autophagy, and signaling pathways that are designed to protect cells from proteotoxicity. In this grant we propose investigation of the role of 3 signaling pathways that are putative proteostasis regulatory mechanisms designed to prevent liver damage, including the insulin and NFκB signaling pathways as well as the regulator of G signaling 16 (RGS16). The proposal is based on preliminary results showing that these 3 pathways are activated in unique ways in several model systems including mammalian cell line and mouse models with inducible expression of ATZ and a novel C. elegans model that facilitates mechanistic interrogation through rapid genetic engineering and drug discovery. We will determine how these pathways are activated and how they affect the hepatic phenotype of ATD by utilizing novel mouse models with targeted disruption of each pathway as well as by pharmacological strategies that influence the pathways. We will also determine whether there is variation in activation of these pathways among individual patients with ATD using iPS-derived hepatocyte cell lines.

描述（由申请人提供）：在 α1 抗胰蛋白酶缺乏症 (ATD) 的经典形式中，点突变会导致肝分泌蛋白的错误折叠，并且变体 1 抗胰蛋白酶 Z (ATZ) 以聚合物和聚集体的形式在肝细胞的 ER 中积累。肝纤维化和肝细胞癌是通过功能获得性“蛋白毒性”机制在受影响的纯合子亚群中发生的。肝脏表型的变异性约 10% 在婴儿期/幼儿期受到影响，而另一个亚组则在 6-7 岁期间通过明显的年龄依赖性过程出现肝病。我们研究的中心假设有 3 个组成部分：1)肝脏表型的变异性由遗传和环境调节因子决定；2) 这些调节因子的目标是 ER 的质量控制机制，它是细胞蛋白质稳态调节网络的一部分；3)抗议机制的主要类型是蛋白质降解途径，例如蛋白酶体和自噬，以及旨在保护细胞免受蛋白质毒性的信号传导途径。在这项资助中，我们建议对 3 种信号传导途径的作用进行研究，这些信号传导途径是旨在保护细胞免受蛋白质毒性的假定的蛋白质稳态调节机制。预防肝损伤，包括胰岛素和 NFκB 信号通路以及 G 信号通路调节器 16 (RGS16)。该提议基于初步结果，表明这 3 条通路在人体内以独特的方式被激活。一些模型系统，包括具有 ATZ 诱导表达的哺乳动物细胞系和小鼠模型，以及一种新的线虫模型，该模型通过快速基因工程和药物发现促进机械询问，我们将确定这些途径如何被激活以及它们如何影响肝脏表型。通过利用新颖的小鼠模型来有针对性地破坏每个通路以及影响这些通路的药理学策略，我们还将使用 iPS 衍生的肝细胞来确定 ATD 患者个体中这些通路的激活是否存在差异。线。