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

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结果的发展。脂肪因子对脂肪组织生理产生局部影响，对肝脏、肺、肌肉和脉管系统产生不利的全身影响。锌指蛋白-36 （ZFP36）是一种mrna结合蛋白，可破坏脂肪因子mrna的稳定性，导致蛋白质表达减少。ZFP36还直接结合并抑制转录因子核因子-:B (NF:B)，这是炎症基因表达的重要激活因子。ZFP36在转录后（通过mRNA结合）和转录后（通过抑制NF:B）改变基因表达的程度尚不清楚。关于ZFP36在脂肪库巨噬细胞和脂肪细胞或动脉粥样硬化病变巨噬细胞泡沫细胞中的功能知之甚少。目前还没有对这些细胞类型的zfp36结合mRNA靶点的全面描述。尽管ZFP36蛋白被预测具有抗炎作用，但尚未研究ZFP36对脂肪因子的脂肪库生产的净影响。目前尚不清楚上调脂肪库或动脉粥样硬化病变巨噬细胞中ZFP36的表达是否会减少炎症性疾病（如动脉粥样硬化或糖尿病）的发生或进展。我们假设ZFP36的高表达会抑制脂肪库和动脉粥样硬化病变中炎性脂肪因子的表达。我们将确定ZFP36的分子靶点，并在体外和小鼠体内测试ZFP36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ZFP36:mRNA相互作用的基因表达变化与依赖于ZFP36介导的NF:B抑制的基因表达变化。我们的小鼠模型系统将在饮食诱导的肥胖小鼠和动脉粥样硬化小鼠中测试高ZFP36表达的影响。我们将测试增强脂肪细胞和巨噬细胞中ZFP36的表达是否可以抑制局部和全身炎症，减轻瘦小鼠和肥胖小鼠不良代谢和动脉粥样硬化结果的发展。本研究的重点是通过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。我们的工作可能将ZFP36确定为肥胖和炎症（包括动脉粥样硬化和糖尿病）加重的重要医疗条件的新治疗靶点。

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.