Treating AT deficiency with drugs that modulate the proteoatasis network

用调节蛋白分解网络的药物治疗 AT 缺陷

• 批准号: 8464402
• 负责人: David H Perlmutter
• 金额: $ 27.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464402
• 关键词: Address; Affect; Age; Autophagocytosis; Breeding; Caenorhabditis elegans; Carbamazepine; Caspase; Cell Line; Cells; Chronic; Cirrhosis; Degradation Pathway; Disease; Endoplasmic Reticulum; Enhancers; Enzymes; Epidemiologic Studies; Fibrosis; Fluphenazine; Future; Gene Expression Profile; Genes; Genetic; Hepatic; Hepatocyte; Hereditary Disease; Histone Deacetylase Inhibitor; Individual; Instruction; Laboratories; Lead; Liver Fibrosis; Liver diseases; Mitochondria; Modeling; NF-kappa B; NFKB Signaling Pathway; Orthologous Gene; Paclitaxel; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Pimozide; Prevention strategy; Primary carcinoma of the liver cells; Protein C Inhibitor; Proteins; Role; Screening procedure; Signal Pathway; Signal Transduction; Sirolimus; Small Interfering RNA; System; TNFRSF5 gene; Tamoxifen; Testing; Therapeutic; Therapeutic Effect; Vorinostat; Work; adeno-associated viral vector; base; caspase 12; coping; design; drug candidate; established cell line; in vivo; inhibitor/antagonist; liver transplantation; loss of function; mouse model; multicatalytic endopeptidase complex; mutant; novel; novel therapeutics; programs; response; small molecule

PROJECT SUMMARY (See instructions): The classical form of al antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease. Liver transplantation represents the only treatment currently available for severe liver disease due to ATD. The liver disease associated with ATD is characterized by a stereotypical chronic fibrosis leading to cirrhosis and hepatocyte hyper-proliferation that predisposes to hepatocellular carcinoma. This pathology is attributed to the proteotoxic effect of mutant AT Z that accumulates in the endoplasmic reticulum (ER) of liver cells, a gain-of-toxic function mechanism specific for the polymerogenic tendencies of mutant ATZ. My lab has elucidated the potential mechanisms by which liver cells cope with the proteotoxic effects of ATZ accumulation in the ER including a distinct set of intracellular degradation pathways (proteasomal and autophagic) and a distinct set of signaling pathways that are specifically activated (autophagy, NFKB, ER- and mitochondrial-caspases but not the unfolded protein response). Our working hypothesis is that pharmacological strategies which capitalize on these naturally occurring, presumably protective proteostasis regulatory mechanisms will have a therapeutic effect on the liver disease caused by ATD. Recently, we validated this hypothesis by showing that an autophagy enhancer drug , carbamazepine (CBZ), promotes degradation of ATZ, reduces the hepatic ATZ load and hepatic fibrosis in vivo in a mouse model of ATD. In the work proposed in this application we will pursue this hypothesis further by investigating other drug candidates with putative actions specifically on the autophagy or on the proteasomal system as well as drug candidates such as histone deacetylase inhibitors which may affect the proteostasis network by broad actions on the cellular transcriptome The project will also capitalize on a C. elegans ATD model-based high content screening platform together with computational pharmacological analyses to discover additional therapeutic candidates. Finally, we will investigate the role of other cellular response pathways, such as NFKB signaling, caspase 12, SIDT2 and PIS kinase, in the pathologic effects of ATD to determine whether these pathways could be exploited for novel therapeutic strategies in the future.

项目摘要（参见说明）：经典形式的抗胰蛋白酶缺乏症 (ATD) 是肝病最常见的遗传原因之一。肝移植是目前治疗 ATD 引起的严重肝病的唯一方法。与 ATD 相关的肝脏疾病的特征是典型的慢性纤维化，导致肝硬化和肝细胞过度增殖，从而诱发肝细胞癌。这种病理学归因于突变体 ATZ 的蛋白毒性作用，该作用在肝细胞的内质网 (ER) 中积累，这是一种针对突变体 ATZ 的聚合倾向的毒性功能获得机制。我的实验室阐明了肝细胞应对内质网 ATZ 积累的蛋白毒性效应的潜在机制，包括一组独特的细胞内降解途径（蛋白酶体和自噬）和一组独特的被特异性激活的信号传导途径（自噬、NFKB、ER-和线粒体半胱天冬酶，但不是未折叠的蛋白质反应）​​。我们的工作假设是，利用这些自然发生的、可能具有保护性的蛋白质稳态调节机制的药理学策略将对 ATD 引起的肝脏疾病产生治疗作用。最近，我们通过在 ATD 小鼠模型中证明自噬增强剂药物卡马西平 (CBZ) 促进 ATZ 降解、降低体内肝脏 ATZ 负荷和肝纤维化来验证了这一假设。在本申请提出的工作中，我们将通过研究对自噬或蛋白酶体系统具有推定作用的其他候选药物以及可能通过对细胞转录组的广泛作用影响蛋白质稳态网络的组蛋白脱乙酰酶抑制剂等候选药物来进一步追求这一假设。该项目还将利用基于线虫 ATD 模型的高内涵筛选平台以及计算药理学分析来发现 其他候选治疗药物。最后，我们将研究其他细胞反应途径，如 NFKB 信号传导、caspase 12、SIDT2 和 PIS 激酶在 ATD 病理效应中的作用，以确定这些途径是否可以在未来用于新的治疗策略。