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: 8636465
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636465
• 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(申请人提供)：脂肪组织衍生免疫因子，全球称为“脂肪因子”，在肥胖症患者中长期升高，并导致包括动脉粥样硬化和糖尿病在内的不良健康后果的发展。脂肪因子对脂肪组织的生理起局部作用，对肝、肺、肌肉和血管系统产生不利的全身作用。锌指蛋白-36(ZFP36)是一种mRNA结合蛋白，能破坏脂肪因子mRNAs的稳定性，导致蛋白表达减少。ZFP36还直接结合和抑制转录因子核因子-B(NF：B)，这是一种重要的炎性基因表达激活因子。ZFP36在转录后(通过mRNA结合)和转录(通过抑制核因子：B)改变基因表达的程度尚不清楚。ZFP36在脂库、巨噬细胞和脂肪细胞以及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，目前还没有关于ZFP36结合的mRNA靶点的全面描述。ZFP36对脂肪仓库产生脂肪因子的净影响尚未被研究，尽管该蛋白被预测为抗炎。目前尚不清楚上调ZFP36在脂肪库或动脉粥样硬化病变的巨噬细胞中的表达是否会减少动脉粥样硬化或糖尿病等炎症性疾病的发生或进展。我们假设ZFP36的高表达将抑制脂肪堆积和动脉粥样硬化病变中的炎性脂肪因子的表达。我们将确定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介导的抑制NF：B的基因表达变化。我们的小鼠模型系统将在饮食诱导的肥胖小鼠和发展为动脉粥样硬化的小鼠中测试高ZFP 36表达的影响。我们将测试增强ZFP36在脂肪细胞和巨噬细胞中的表达是否可以抑制局部和全身炎症，并缓解瘦小和肥胖小鼠不良代谢和动脉粥样硬化结果的发展。这项建议侧重于一种新的机制，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。我们的工作可能确定ZFP36作为一种新的治疗靶点，用于治疗因肥胖和炎症(包括动脉粥样硬化和糖尿病)而加剧的重要疾病。