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。已经鉴定了100多个可以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依赖的转录机制。最近，我们确定了一种新的转录机制，FOXO 4调节平滑肌细胞（SMC）表型和基质金属蛋白酶9（MMP 9）和Toll样受体4（TLR 4）的转录。由于SMC表型调节、MMP 9和TLR 4参与动脉粥样硬化形成，我们认为FOXO 4通过这些效应物促进动脉粥样硬化。提出了三个具体目标。(1)表征调节FOXO 4活性的信号通路。我们将研究FOXO 4是否介导JNK激活的MMP 9转录，以及JAK/STAT信号是否通过PIM激酶使FOXO 4失活来抑制MMP 9转录。(2)探讨FOXO 4在TLR 4转录激活中的作用。我们将研究FOXO 4激活TLR转录的分子机制，并检查FOXO 4上调TLR 4是否足以促进TLR 4介导的促炎细胞因子的产生。我们还将研究FOXO 4是否在单核细胞向巨噬细胞分化过程中发挥作用。(3)确定FOXO 4是否以及如何促进动脉粥样硬化。我们将测试Foxo 4在apoE缺失小鼠中的失活是否减少动脉粥样硬化，以及Foxo 4是否通过下游效应物（TLR 4、MMP 9）和/或SMC表型调节来影响动脉粥样硬化。心血管疾病患者对降脂药物缺乏反应，这强调了需要确定新的治疗动脉粥样硬化的治疗靶点。FOXO 4是一个有前途的治疗干预的目标，因为抑制FOXO 4活性可以减少TLR 4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。实现本建议中的具体目标将为评估这一可能性提供基础。虽然我们在这项提案中的重点是了解FOXO 4在动脉粥样硬化中的作用，但对特定目标1和2的研究也将有助于我们了解FOXO 4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MMP 9和/或TLR 4也涉及这些疾病的发病机制。

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.