Role of FOXO4 in atherosclerosis

描述(申请人提供)：动脉粥样硬化并发症是发达国家死亡的主要原因。目前已鉴定出100多个影响动脉粥样硬化形成的基因。我们的长期目标是阐明这些基因依赖于信号的转录机制。最近，我们发现了一种新的转录机制，通过FOXO4调节平滑肌细胞(SMC)表型和基质金属蛋白酶9(MMP9)和Toll样受体4(TLR4)的转录。由于SMC表型调节、MMP9和TLR4参与了动脉粥样硬化的形成，我们认为FOXO4通过这些效应分子参与动脉粥样硬化的形成。提出了三个具体目标。(1)研究调控FOXO4活性的信号通路。我们将研究FOXO4是否介导JNK激活的MMP9转录，以及JAK/STAT信号是否通过PIM激酶失活FOXO4来抑制MMP9转录。(2)探讨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，并检验FOXO4上调TLR4是否足以促进TLR4介导的促炎细胞因子的产生。我们还将研究FOXO4是否在单核细胞向巨噬细胞分化过程中发挥作用。(3)确定FOXO4是否促进动脉粥样硬化以及如何促进动脉粥样硬化。我们将测试在apoE缺失小鼠中灭活FOXO4是否可以减少动脉粥样硬化，以及FOXO4是否通过下游效应因子(TLR4，MMP9)和/或SMC表型调节影响动脉粥样硬化。心血管疾病患者对降脂药物缺乏反应，强调了确定治疗动脉粥样硬化的新靶点的必要性。FOXO4是一个有希望的治疗干预靶点，因为抑制FOXO4活性可以减少TLR4诱导的细胞因子的产生，减少内膜增厚，并稳定晚期动脉粥样硬化斑块。实现这项提案中的具体目标将为评估这一可能性提供基础。虽然我们的重点是了解FOXO4在动脉粥样硬化中的作用，但对特定目标1和2的研究也将帮助我们了解FOXO4在其他人类疾病中的作用，如类风湿性关节炎、多发性硬化症和癌症，因为MMP9和/或TLR4也与这些疾病的发病机制有关。

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.