Atherogenic Patheways Mediated by FOXO

FOXO 介导的致动脉粥样硬化通路

• 批准号: 7329717
• 负责人: DOMENICO ACCILI
• 金额: $ 55.45万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329717
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Acetylation; Address; Adipocytes; Affect; Apolipoproteins B; Apoptosis; Atherosclerosis; Binding; CD36 gene; Cardiovascular Diseases; Cause of Death; Cholesterol; Data; Deacetylase; Development; Diabetes Mellitus; Dyslipidemias; Family; Gene Expression; Gene Expression Regulation; Genetic Transcription; Glucose; Heart Diseases; Hepatic; Histones; Hyperglycemia; Individual; Induction of Apoptosis; Insulin; Insulin Receptor; Insulin Resistance; Investigation; Knock-in Mouse; Kupffer Cells; Laboratories; Ligation; Link; Lipids; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Macrophage Cell Biology; Maps; Mediating; Metabolic; Metabolic syndrome; Metabolism; Modeling; Modification; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Organ; PAWR protein; Patients; Phosphorylation; Positioning Attribute; Predisposition; Process; Property; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogenes; Pyruvate; Pyruvates; RNA; Regulatory Element; Role; Signal Transduction; Site; Sterols; Stress; Tail; Testing; Tissue Model; Tissues; Triglycerides; Very low density lipoprotein; atherogenesis; base; cell type; deprivation; diabetic; experience; forkhead protein; in vivo; inorganic phosphate; interest; lifetime risk; lipid metabolism; loss of function; macrophage; mutant; novel strategies; oxidation; research study; response

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.

动脉粥样硬化及其并发症发生较早，代谢患者更为严重 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。这 胰岛素抵抗和高血糖加速性动脉粥样硬化的机制尚不清楚，也不清楚 这些代谢异常的部位促进了已知的动脉粥样硬化。 PI已经发展 组织特异性胰岛素抵抗的模型，并建立了信号级联，胰岛素调节 通过叉子转录因子FOXO1的基因表达。提出的PPG代表理想场所 将PI在胰岛素作用和胰岛素抵抗模型中的经验与高个子的专业知识相结合 和塔巴斯实验室在肝脂蛋白周转率，巨噬细胞生物学和 动脉粥样硬化。该项目有两个具体的目标：AIM 1将研究FOXO1依赖性的机制 肝中的动脉粥样硬化血脂异常。 PI将检验以下假设，即肝胰岛素抵抗通过 FOXO1促进动脉粥样硬化脂质谱，并增加了VLDL APOB分泌。提议 实验将研究增加FOXOI依赖性转录对甘油三酸酯合成的影响， FFA氧化和脂蛋白更新。体内研究将解决FOXOI是否可以调节 对动脉粥样硬化的敏感性以及高血糖对FOXOI活性的作用。 AIM 2将检查角色 巨噬细胞胆固醇载荷诱导未折叠的蛋白质反应（UPR）的FOXO1/3。 胆固醇加载和SRA结扎诱导巨噬细胞UPR。如Drs的初步研究所示。高的 和TABAS，巨噬细胞中的胰岛素抵抗会增加胆固醇诱导的凋亡的敏感性。 此过程与CD36，SRA和CHOP表达增加以及Akt和Akt的降低有关 FOXO磷酸化。 PI将产生FOXO1/3缺陷巨噬细胞，以检查改变的影响 FOXOI/3在胆固醇引起的UPR和动脉粥样硬化上的表达。 PI将使用RNA分析 FOXOI/3缺陷巨噬细胞以绘制Foxo转录目标并将此信息整合到 塔巴斯和高个子项目中巨噬细胞FOXO1/3的功能分析。这些的结果 调查是为胰岛素抵抗和脂质异常治疗的新方法 基于肝脏和巨噬细胞中FOXO活性的调节2型糖尿病。