Role of FOXO4 in atherosclerosis

FOXO4 在动脉粥样硬化中的作用

• 批准号: 7135207
• 负责人: Zhi-Ping Liu
• 金额: $ 35.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135207
• 关键词: JAK kinase; JUN kinase; apolipoprotein E; atherosclerosis; biological signal transduction; cell differentiation; cytokine; enzyme activity; gel mobility shift assay; gene expression; genetic promoter element; genetically modified animals; inflammation; laboratory mouse; macrophage; metalloendopeptidases; phorbols; toll like receptor; transcription factor; vascular endothelium; vascular smooth muscle

DESCRIPTION (provided by applicant): Complications of atherosclerosis are the leading cause of mortality in developed countries. More than 100 genes that can influence atherogenesis have been identified. Our long-term goals are to elucidate the signaling dependent transcriptional mechanisms of these genes. Recently, we identified a novel transcriptional mechanism by which FOXO4 regulates smooth muscle cell (SMC) phenotypes and transcription of matrix metalloproteinase 9 (MMP9) and Toll-like-receptor 4 (TLR4). As SMC phenotypic modulation, MMP9, and TLR4 are involved in atherogenesis, we propose that FOXO4 contributes to atherosclerosis through these effectors. Three specific aims are proposed. (1) To characterize the signaling pathways that regulate FOXO4 activities. We will investigate whether FOXO4 mediates JNK-activated MMP9 transcription and whether JAK/STAT signaling suppresses MMP9 transcription through inactivation of FOXO4 by PIM kinases. (2) To investigate the role of FOXO4 in transcriptional activation of TLR4. We will study the molecular mechanism by which FOXO4 activates TLR transcription and examine whether upregulation of TLR4 by FOXO4 is sufficient to promote TLR4-mediated proinflammatory cytokine production. We will also investigate whether FOXO4 plays a role during monocyte to macrophage differentiation. (3) To determine whether and how FOXO4 promotes atherosclerosis. We will test whether inactivation of Foxo4 in apoE-null mice reduces atherosclerosis and whether Foxo4 influences atherosclerosis through downstream effectors (TLR4, MMP9), and/or SMC phenotypic modulation. The lack of response to lipid-lowering drugs in patients with cardiovascular disease emphasizes the need to identify new therapeutic targets for the treatment of atherosclerosis. FOXO4 is a promising target for therapeutic intervention since inhibition of FOXO4 activity may reduce TLR4-induced cytokine production, reduce intimal thickening, and stabilize late atherosclerotic plaques. Accomplishing the specific aims in this proposal will provide the foundation to assess this possibility. While our focus in this proposal is to understand the role of FOXO4 in atherosclerosis, studies of the specific aims 1 & 2 will also help us to understand the role of FOXO4 in other human diseases such as rheumatoid arthritis, multiple sclerosis, and cancer, as MMP9 and/or TLR4 are implicated in the pathogenesis of these diseases as well.

描述（由申请人提供）：动脉粥样硬化的并发症是发达国家死亡率的主要原因。已经鉴定出可能影响动脉粥样硬化的100多个基因。我们的长期目标是阐明这些基因的信号依赖性转录机制。最近，我们确定了一种新型的转录机制，FOXO4通过该机制调节平滑肌细胞（SMC）表型以及基质金属蛋白酶9（MMP9）和Toll-like-tike-epector-4（TLR4）的转录。由于SMC表型调节，MMP9和TLR4参与动脉粥样硬化，我们建议FOXO4通过这些效应子有助于动脉粥样硬化。提出了三个具体目标。 （1）表征调节FOXO4活动的信号通路。我们将研究FOXO4介导JNK激活的MMP9转录以及JAK/STAT信号是否通过PIM激酶对FOXO4的失活来抑制MMP9转录。 （2）研究FOXO4在TLR4转录激活中的作用。我们将研究FOXO4激活TLR转录的分子机制，并检查FOXO4对TLR4的上调是否足以促进TLR4介导的促炎性细胞因子产生。我们还将研究FOXO4在单核细胞中是否起作用巨噬细胞分化。 （3）确定FOXO4是否促进动脉粥样硬化。我们将测试APOE-NULL小鼠中FOXO4的灭活是否会减少动脉粥样硬化，而FOXO4是否通过下游效应子（TLR4，MMP9）和/或SMC表型调节来影响动脉粥样硬化。心血管疾病患者中缺乏对降低脂质药物的反应，强调需要确定治疗动脉粥样硬化的新治疗靶标。 FOXO4是治疗干预的有希望的靶标，因为抑制FOXO4活性可能会减少TLR4诱导的细胞因子产生，减少内膜增厚并稳定晚期动脉粥样硬化斑块。在此提案中实现具体目标将为评估这种可能性提供基础。虽然我们在这一建议上的重点是了解FOXO4在动脉粥样硬化中的作用，但对特定目的1和2的研究也将有助于我们了解FOXO4在其他人类疾病中的作用，例如类风湿关节炎，多发性硬化症和癌症，例如MMP9和/或TLR4，也涉及这些疾病的发病机制。