Targeting beta-catenin in liver pathology: Novel Interactions, Novel Paradigms

靶向肝脏病理学中的 β-连环蛋白：新的相互作用，新的范式

• 批准号: 8690843
• 负责人: Satdarshan Singh Monga
• 金额: $ 32.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690843
• 关键词: Accounting; Address; Adherens Junction; Adverse effects; Affect; Anabolism; Antioxidants; Ascorbic Acid; Biological; Biological Assay; Biological Process; Biology; CTNNB1 gene; Cell Adhesion; Cell Proliferation; Cell-Cell Adhesion; Cyclic AMP-Dependent Protein Kinases; Death Rate; Development; Diethylnitrosamine; Down-Regulation; Equilibrium; Event; Exons; Exposure to; Felis catus; Generations; Grant; Growth; Hepatic; Hepatoblastoma; Hepatocarcinogenesis; Hepatocyte; Human; In Vitro; Incidence; Injury; Investigation; Knockout Mice; Lead; Liver; Liver Fibrosis; Malignant Neoplasms; Medicine; Metabolic syndrome; Metabolism; Molecular; Morphologic artifacts; Mus; Natural regeneration; Outcome; Oxidative Stress; PDGFRB gene; PTPN11 gene; Pathology; Pathway interactions; Patient Selection; Phosphorylation; Primary carcinoma of the liver cells; Primates; Process; Proteins; Regulation; Reporting; Research Proposals; Rodent; Role; Serine; Serine/Threonine Phosphorylation; Serum; Signal Pathway; Signal Transduction; Site; Somatic Mutation; Testing; Threonine; Up-Regulation; Ursidae Family; arm; ascorbate; base; beta catenin; cancer cell; cancer therapy; chemical carcinogen; dietary supplements; hepatoma cell; in vivo; liver injury; novel; prevent; public health relevance; research study; therapeutic target; therapy resistant; tumorigenesis

DESCRIPTION (provided by applicant): Wnt/¿-catenin signaling is pertinent in liver biology in regulating zonation, regeneration, development and metabolism. However aberrations in this pathway have been reported in hepatic fibrosis, hepatic injury, hepatoblastomas and hepatocellular cancer (HCC). Targeting ¿ -catenin in HCC is imminent. It is the 3rd fatal cancer worldwide and its incidence and associated death rates have steadily increased since the 1980s. Cellular & molecular basis of HCC is poorly understood. Wnt signaling has been deemed active in 17-40% of HCCs due to various reasons and around 20-40% of all HCCs harbor monoallelic somatic mutations in the exon-3 of the ¿-catenin gene (CTNNB1) that encodes for a non-serine/threonine phosphorylatable, stable and constitutively active protein, making it an attractive therapeutic target. We have made several important and some paradoxical observations over the last few years including identification of novel interactions and cross-regulations between ¿ -catenin and other molecules. These may have significant biological and translational implications mandating an in-depth analysis that may have widespread implications in not just HCC but other hepatic pathologies where ¿ -catenin targeting may be of essence such as hepatic fibrosis, injury and metabolic syndrome. The overarching hypothesis of the proposal is that therapeutic targeting of ¿ -catenin must take into account existing redundancies and crosstalk with specific signaling pathways, which need to be comprehensively elucidated. We will test these hypotheses in three distinct but thematically related aims. In aim 1, we will investigate the mechanism of oxidative stress dependent enhanced hepatocarcinogenesis in ¿ -catenin conditional knockout mice (Hep- ¿ -Cat KO) to address if enhanced HCC is a murine 'artifact' due to the role of - ¿ catenin in vitamin C biosynthesis in murine hepatocytes. We identified a novel role of ¿ -catenin signaling in vitamin C biosynthesis in the murine liver, whic is a known major antioxidant. Unlike humans and primates, rodents synthesize vitamin C in the hepatocytes and regular mouse chow is devoid of ascorbic acid. We hypothesize that increased HCC and oxidative stress in Hep- ¿ -Cat KO is due to compromised vitamin C biosynthesis and its normalization will alleviate HCC and demonstrate ¿ -catenin to be a global therapeutic target in HCC. In aim 2 we will investigate mechanism and biological implications of PDGFR¿ upregulation and activation after ¿-catenin inhibition in HCC cells. We hypothesize that PDGFR¿ upregulation along with the activation of its specific downstream signaling arm is an important mechanism that will allow growth of HCC after ¿-catenin inhibition and that understanding the role and regulation of this phenomena will bear significantly on efficacious HCC treatment. In aim 3, we will investigate the role and regulation of ?-catenin stabilization following inhibition of ¿-catenin expression in the liver. We hypothesize that ?-catenin stabilization during ¿-catenin inhibition in HCC will prevent any untoward effect related to disruption of cell-cell adhesion. All the proposed studies in the grant will utilize a balance of i vitro and in vivo set of experiments and the expected outcomes will be highly relevant and translational.

描述（由应用程序提供）：Wnt/�-蛋白蛋白信号在注册区，再生，发展和代谢中的肝脏生物学中相关。然而，在肝纤维化，肝损伤，肝细胞瘤和肝细胞癌（HCC）中，该途径中的畸变已有报道。 HCC中的靶向�-蛋白蛋白即将到来。它是全球第三次致命癌，自1980年代以来，其事件和相关的死亡率已悄悄提高。 HCC的细胞和分子基础知之甚少。由于各种原因，Wnt信号传导在17-40％的HCC中被视为活跃，并且在所有HCC中的20-40％携带了单相3的单相体突变突变中的 - - 钙蛋白基因（CTNNB1），这些突变（CTNNB1）编码非丝氨酸磷酸磷酸盐/磷酸磷酸化的目标，并具有稳定的有吸引力的构造，使其具有稳定性的范围。在过去的几年中，我们进行了一些重要的和一些矛盾的观察，包括鉴定 - - 卡宁蛋白和其他分子之间的新型相互作用和交叉调节。这些可能具有重大的生物学和翻译意义，该含义强制进行深入分析，这可能不仅在HCC中具有宽度的意义，而且在其他肝病病理学中可能具有 - 钙蛋白靶向的其他本质上可​​能是肝纤维化，损伤，损伤和代谢综合征。该提案的总体假设是 - 帕宁蛋白的治疗靶向必须考虑到现有的冗余和串扰，并与特定的信号通路进行了串扰，这需要全面阐明。我们将以三种不同但主题相关的目的来检验这些假设。在AIM 1中，我们将调查氧化胁迫依赖性的机理 - 在� -catenin条件敲除小鼠（Hep-€-CAT KO）中，肝癌的增强，以解决是否增强的HCC是否是鼠类的“人为”，这是由于-Catenin in -Catenin in -catenin in -catenin in Vivimin c catenin in Vivamin c Biosynthessis在Murine herpatocatocatocatocatocatocatocatocatocatocatoctocatocysesses s s s seplysessessis中的作用。我们确定了 - - 钙蛋白信号传导在鼠肝脏中维生素C生物合成中的新作用，WHIC是已知的主要抗氧化剂。与人类和私人不同，啮齿动物在肝细胞中合成维生素C，而常规小鼠食物没有抗坏血酸。我们假设HEP - CAT KO中的HCC和氧化应激增加是由于维生素C生物合成受损及其归一化将减轻HCC，并证明� -Catenin是HCC中的全球治疗靶标。在AIM 2中，我们将研究hcc细胞中PDGFR¿上调和激活的机制和生物学意义。我们假设PDGFR¿上调以及其特定的下游信号传导组的激活是一种重要的机制，它将允许hcatenin抑制后HCC的生长，并且了解这种现象的作用和调节将对有效的HCC治疗产生显着影响。在AIM 3中，我们将调查肝脏中 - 钙蛋白表达的作用和调节。我们假设在HCC中抑制 - 蛋白抑制期间的稳定蛋白会阻止与细胞细胞粘附破坏有关的任何不良效应。赠款中所有提出的研究都将利用体外和体内实验集的平衡，预期的结果将是高度相关和转化的。