Atherogenic Patheways Mediated by FOXO

动脉粥样硬化及其并发症发生较早，在代谢紊乱的患者中更为严重。 综合征和2型糖尿病。心脏病是糖尿病患者死亡的主要原因。的 胰岛素抵抗和高血糖加速动脉粥样硬化的机制尚不清楚， 这些代谢异常促进动脉粥样硬化形成的部位是已知的。PI开发了 组织特异性胰岛素抵抗模型，并建立了胰岛素调节的信号级联反应 通过叉头转录因子FoxO 1的基因表达。拟议的PPG是一个理想的场所， 将Pi在胰岛素作用和胰岛素抵抗模型方面的经验与Tall 和塔巴斯实验室在肝脂蛋白周转、巨噬细胞生物学和 动脉粥样硬化本项目有两个具体目标：目标1将研究FoxO 1依赖性的 肝动脉粥样硬化性血脂异常。PI将检验肝脏胰岛素抵抗通过以下途径起作用的假设： FoxO 1促进致动脉粥样硬化脂质谱，增加VLDL ApoB分泌。拟议 实验将研究增加的FoxOI依赖性转录对甘油三酯合成的影响， FFA氧化和脂蛋白周转。体内研究将解决FoxOI是否可以调节 动脉粥样硬化易感性和高血糖对FoxOI活性的作用目标2将研究 FoxO 1/3在巨噬细胞胆固醇负荷诱导未折叠蛋白反应（UPR）中的作用。 胆固醇负荷和SRA连接诱导巨噬细胞UPR。根据Tall博士的初步研究， 和塔巴斯，巨噬细胞中的胰岛素抗性增加了对胆固醇诱导的细胞凋亡的易感性。 这一过程与CD 36、SRA和CHOP表达增加以及AKT和THP表达减少有关。 FoxO磷酸化。PI将产生FoxO 1/3缺陷的巨噬细胞，以检查改变的细胞因子的作用。 FoxOI/3在胆固醇诱导的UPR和动脉粥样硬化中的表达PI将使用RNA分析 FoxOI/3缺陷型巨噬细胞定位FoxO转录靶标并将该信息与 巨噬细胞FoxO 1/3在塔巴斯和Tall项目中的功能分析。这些的结果 研究的目的是提供治疗胰岛素抵抗中脂质异常的新方法， 基于肝脏和巨噬细胞中FoxO活性的调节的2型糖尿病。

Atherosclerosis and its complications occur earlier and are more severe in patients with the metabolic syndrome and type 2 diabetes. Heart disease is the leading cause of death among diabetics. The mechanisms by which insulin resistance and hyperglycemia accelerate atherosclerosis are not clear, nor are the sites at which these metabolic abnormalities promote atherogenesis known. The PI has developed models of tissue-specific insulin resistance and established a signaling cascade by which insulin regulates gene expression via the forkhead transcription factor FoxO1. The proposed PPG represents an ideal venue to integrate the Pi's experience in insulin action and models of insulin resistance with the expertise of the Tall and Tabas laboratories in studies of hepatic lipoprotein turnover, macrophage cell biology and atherosclerosis. This project has two Specific Aims: Aim 1 will investigate mechanism of FoxO1-dependent atherogenic dyslipidemia in liver. The PI will test the hypothesis that hepatic insulin resistance acts through FoxO1 to promote an atherogenic lipid profile, with increased VLDL ApoB secretion. The proposed experiments will investigate the effects of increased FoxOI-dependent transcription on triglyceride synthesis, FFA oxidation and lipoprotein turnover. In vivo studies will address whether FoxOI can modulate the susceptibilty to atherosclerosis and the role of hyperglycemia on FoxOI activity. Aim 2 will examine the role of FoxO1/3 in the induction of Unfolded Protein Response (UPR) by cholesterol loading of macrophages. Cholesterol loading and SRA ligation induce macrophage UPR. As shown in preliminary studies by Drs. Tall and Tabas, insulin resistance in the macrophage increases susceptibility to cholesterol-induced apoptosis. This process is associated with increased CD36, SRA and CHOP expression, as well as decreased AKT and FoxO phosphorylation. The PI will generate FoxO1/3-deficient macrophages to examine the effect of altered FoxOI/3 expression on cholesterol-induced UPR and atherosclerosis. The PI will use RNA profiling of FoxOI/3-deficient macrophage to map the FoxO transcriptional targets and integrate this information with the functional analysis of macrophage FoxO1/3 in the Tabas and Tall projects. The upshot of these investigations is to provide new approaches to the therapy of lipid abnormalities in insulin resistance and type 2 diabetes based on the modulation of FoxO activity in liver and macrophages.