The anti-inflammatory mRNA-binding protein ZFP36 in Obesity and Metabolism

抗炎 mRNA 结合蛋白 ZFP36 在肥胖和代谢中的作用

• 批准号: 8824524
• 负责人: CALEB BENJAMIN KALLEN
• 金额: $ 32.56万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824524
• 关键词: Adipocytes; Adipose tissue; American; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Aorta; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Binding; Binding Proteins; Biological Models; Biological Process; Blood Vessels; Cells; Complement Factor B; Development; Diabetes Mellitus; Diet; Disease; Eating; FABP4 gene; Fatty acid glycerol esters; Foam Cells; Gene Expression; Gene Expression Profiling; Goals; Health; Immune; Immunohistochemistry; Immunoprecipitation; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Liver; Lung; Measures; Mediating; Medical; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Molecular; Molecular Target; Mus; Muscle; Mutate; Myocardial Infarction; Nuclear; Obese Mice; Obesity; Outcome; Overweight; Physiology; Production; Proteins; RNA; Research; Reverse Transcription; Siblings; System; TIS11 protein; Testing; Tissues; Transcript; Transgenic Mice; Weight Gain; Work; Zinc Fingers; adipokines; atherogenesis; base; cell type; chemokine; cytokine; feeding; glucose disposal; improved; insulin sensitivity; mRNA Stability; macrophage; mouse model; new therapeutic target; prevent; promoter; protein expression; research study; response; transcription factor

DESCRIPTION (provided by applicant): Adipose tissue-derived immune factors, globally referred to as "adipokines," are chronically elevated in obesity and contribute to the development of adverse health outcomes including atherosclerosis and diabetes. Adipokines exert local effects on adipose tissue physiology and unfavorable systemic effects on liver, lung, muscle, and the vasculature. Zinc Finger Protein-36 (ZFP36) is an mRNA-binding protein that destabilizes adipokine mRNAs leading to reduced protein expression. ZFP36 also directly binds and represses the transcription factor nuclear factor-:B (NF:B), an important activator of inflammatory gene expression. The extent to which ZFP36 alters gene expression post-transcriptionally (via mRNA binding) vs. transcriptionally (via inhibition of NF:B) is unknown. Little is known about the function of ZFP36 in adipose depot macrophages and adipocytes or in macrophage foam cells of atherosclerotic lesions. No comprehensive description of ZFP36-bound mRNA targets exists for these cell types. The net effects of ZFP36 on adipose depot production of adipokines have not been studied although the protein is predicted to be anti-inflammatory. It is unknown whether up-regulating ZFP36 expression in the adipose depot or in macrophages of atherosclerotic lesions will reduce the development or progression of inflammatory disorders such as atherosclerosis or diabetes. We hypothesize that high ZFP36 expression will repress inflammatory adipokine expression in adipose depots and in atherosclerotic lesions. We will identify the molecular targets of ZFP36 and test the biological functions of ZFP36 in adipocytes and macrophages in vitro and in mice. We will distinguish gene expression changes that depend upon ZFP36:mRNA interactions from those that depend upon ZFP36-mediated inhibition of NF:B. Our mouse model systems will test the effects of high ZFP36 expression in diet-induced obese mice and in mice that develop atherosclerosis. We will test whether enhancing ZFP36 expression in adipocytes and macrophages can suppress local and systemic inflammation and mitigate the development of adverse metabolic and atherogenic outcomes in lean and obese mice. This proposal focuses on a new mechanism for regulating systemic inflammatory responses by targeting adipokine mRNA stability in fat and vascular tissues. Our work may identify ZFP36 as a new therapeutic target for important medical conditions exacerbated by obesity and inflammation including atherosclerosis and diabetes.

描述（由申请人提供）：脂肪组织来源的免疫因子，全球称为“脂肪因子”，在肥胖症中长期升高，并导致不良健康结局的发展，包括动脉粥样硬化和糖尿病。脂肪因子对脂肪组织生理产生局部作用，对肝、肺、肌肉和脉管系统产生不利的全身作用。锌指蛋白-36（ZFP 36）是一种mRNA结合蛋白，其使脂肪因子mRNA不稳定，导致蛋白质表达减少。ZFP 36还直接结合并抑制转录因子核因子-：B（NF：B），其是炎性基因表达的重要激活剂。ZFP 36在转录后（通过mRNA结合）与转录（通过抑制NF：B）改变基因表达的程度尚不清楚。关于ZFP 36在脂肪贮库巨噬细胞和脂肪细胞或在动脉粥样硬化病变的巨噬细胞泡沫细胞中的功能知之甚少。对于这些细胞类型，不存在ZFP 36结合的mRNA靶标的全面描述。ZFP 36对脂肪因子的脂肪贮库产生的净效应尚未研究，尽管预测该蛋白质是抗炎的。尚不清楚在动脉粥样硬化病变的脂肪库或巨噬细胞中上调ZFP 36表达是否会减少炎性疾病如动脉粥样硬化或糖尿病的发展或进展。我们假设ZFP 36高表达将抑制脂肪库和动脉粥样硬化病变中炎性脂肪因子的表达。我们将鉴定ZFP 36的分子靶点，并在体外和小鼠体内测试ZFP 36在脂肪细胞和巨噬细胞中的生物学功能。我们将区分依赖于ZFP 36：mRNA相互作用的基因表达变化与依赖于ZFP 36介导的NF：B抑制的基因表达变化。我们的小鼠模型系统将测试ZFP 36高表达在饮食诱导的肥胖小鼠和发展动脉粥样硬化的小鼠中的作用。我们将测试在瘦和肥胖小鼠中增强脂肪细胞和巨噬细胞中的ZFP 36表达是否可以抑制局部和全身炎症，并减轻不良代谢和致动脉粥样硬化结果的发展。该提案的重点是通过靶向脂肪和血管组织中脂肪因子mRNA的稳定性来调节全身炎症反应的新机制。我们的工作可能会将ZFP 36确定为肥胖和炎症加剧的重要疾病（包括动脉粥样硬化和糖尿病）的新治疗靶点。