Modulation of liver cancer by PPARbeta/delta

PPARbeta/delta 对肝癌的调节

• 批准号: 8461642
• 负责人: Jeffrey M Peters
• 金额: $ 27.47万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-04 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461642
• 关键词: Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; CCAAT-Enhancer-Binding Proteins; Cell Adhesion Molecules; Cessation of life; Chronic; Coupled; DNA Binding Domain; Data; Diethylnitrosamine; Disease; Epigenetic Process; Etiology; Frequencies; Gene Targeting; Goals; Hepatitis C virus; Hepatocarcinogenesis; Hepatotoxicity; Homeostasis; Incidence; Inflammation; Inflammatory; Knockout Mice; Kupffer Cells; Lead; Ligands; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Molecular; Molecular Target; Nuclear Hormone Receptors; Nuclear Receptors; Operative Surgical Procedures; PPAR-beta; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phase; Premalignant; Prevention; Primary carcinoma of the liver cells; Process; Role; STAT3 gene; Signal Transduction; Signaling Molecule; Testing; Transgenic Mice; Transgenic Model; Tumor Promotion; United States; Up-Regulation; Work; attenuation; cancer type; cell type; chemokine; chemotherapy; cytokine; human mortality; inflammatory modulation; innovation; mortality; mutant; novel strategies; prevent; public health relevance; receptor; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): There are more than 14,000 deaths per year due to liver cancer, the most rapidly increasing type of cancer in the United States. In contrast to other cancers, liver cancer frequency and mortality is increasing. There is a distinct need for new approaches to prevent and treat this disease as the current strategies of chemotherapy and surgical treatments are not very effective. Thus, it is essential to delineate new molecular pathways involved in the etiology of liver cancer to provide new strategies with significantly better efficacy to prevent human mortality due to liver cancer. It well established that direct transcriptional up-regulation of target genes by peroxisome proliferator-activated receptor-/ (PPAR/) can modulate cellular homeostasis. However, there is also evidence that PPAR/ has epigenetic activities that include inhibiting expression of proinflammatory cytokines, chemokines and cell adhesion molecules via interacting with other transcription factors. Preliminary data demonstrates that PPAR/ can attenuate liver toxicity and pre-malignant liver tumor formation. Further, ligand activation of PPAR/ can attenuate liver toxicity by down-regulating pro- inflammatory signaling molecules. The central hypothesis of this proposal is that PPAR/ can be specifically targeted to inhibit hepatocarcinogenesis. Aim 1 will test the hypothesis that PPAR/ attenuates tumor promotion during hepatocarcinogenesis. This will be examined by inducing liver cancer using either a chemically-induced model or an HCV-transgenic model using both wild-type and Ppar/-null mice, coupled with treatment with the high affinity PPAR/ ligand GW0742. Aim 2 will test the hypothesis that PPAR/ attenuates tumor promotion by epigenetic modulation of inflammatory signaling in Kupffer cells. This will be examined by analysis of transgenic mice expressing a DNA binding domain mutant form of PPAR/ that can epigenetically interact with other transcription factors, but is incapable of activating PPRE-specific target genes. This analysis will also be coupled with analysis of conditional deletion of PPAR/ in Kupffer cells. Results from these innovative studies will determine if PPAR/ can be an anti-inflammatory molecular target and provide an alternative strategy for preventing and treating liver cancer. Additionally, results from these studies could lead to a significant paradigm shift in treatment strategies for liver cancer and other chronic inflammatory diseases if epigenetic modulation of inflammatory signaling mediated by PPAR/ is shown to effectively prevent hepatocarcinogenesis.

描述（由申请人提供）：由于肝癌，每年有14,000多人死亡，这是美国最快增加的癌症类型。与其他癌症相反，肝癌的频率和死亡率正在增加。由于当前的化学疗法和手术疗法的策略不是很有效，因此明显需要采用新方法来预防和治疗这种疾病。因此，至关重要的是，要描述参与肝癌病因的新分子途径，以提供具有更高疗效的新策略，以防止由于肝癌引起的人类死亡率。可以很好地确定，通过过氧化物酶体增殖物激活的受体 - /（PPAR/）直接转录靶基因可以调节细胞稳态。但是，也有证据表明，PPAR/具有表观遗传活性，包括抑制促炎细胞因子，趋化因子和细胞粘附分子的表达，通过与其他转录因子相互作用。初步数据表明，PPAR/可以减弱肝脏毒性和恶性前肝肿瘤的形成。此外，PPAR/ PPAR的配体激活可以通过下调炎性信号分子来减轻肝脏毒性。该提议的中心假设是PPAR/可以专门针对抑制肝癌发生。 AIM 1将检验以下假设：肝癌发生过程中PPAR/减弱肿瘤促进的假设。这将通过使用化学诱导的模型或使用野生型和pPAR/ -NULL小鼠诱导肝癌或HCV转基因模型来检查这一点，并与高亲和力PPAR/配体GW0742一起处理。 AIM 2将检验以下假设：PPAR/ PPAR通过kupffer细胞中炎症信号的表观遗传调节来促进肿瘤。这将通过对表达DNA结合结构域突变体的PPAR/可以表观遗传与其他转录因子相互作用的转基因小鼠进行分析，但无法激活PPRE特异性靶基因。该分析还将与库普弗细胞中PPAR/ PPAR的条件缺失分析相结合。这些创新研究的结果将确定PPAR/是否可以是抗炎分子靶标，并提供预防和治疗肝癌的替代策略。此外，如果这些研究的结果可能导致肝癌和其他慢性炎症性疾病的治疗策略的显着范式转移，如果PPAR介导的炎症信号的表观遗传调节被证明可有效防止肝癌发生。