Role of FOXO4 in atherosclerosis

描述（由申请人提供）：动脉粥样硬化并发症是发达国家死亡的主要原因。已鉴定出 100 多个可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的信号传导依赖性转录机制。最近，我们发现了一种新的转录机制，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 样受体 4 (TLR4) 的转录。由于 SMC 表型调节、MMP9 和 TLR4 参与动脉粥样硬化形成，因此我们提出 FOXO4 通过这些效应子促进动脉粥样硬化。提出了三个具体目标。 (1) 表征调节 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 信号传导是否通过 PIM 激酶灭活 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，并检查FOXO4对TLR4的上调是否足以促进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是否以及如何促进动脉粥样硬化。我们将测试 apoE 缺失小鼠中 Foxo4 失活是否会减少动脉粥样硬化，以及 Foxo4 是否通过下游效应器（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需要确定治疗动脉粥样硬化的新治疗靶点。 FOXO4 是一个有前途的治疗干预靶点，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。实现本提案中的具体目标将为评估这种可能性提供基础。虽然我们本提案的重点是了解 FOXO4 在动脉粥样硬化中的作用，但对具体目标 1 和 2 的研究也将帮助我们了解 FOXO4 在其他人类疾病（如类风湿关节炎、多发性硬化症和癌症）中的作用，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.