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

描述(由申请人提供)：肥胖会产生一种全身炎症状态，与不利的健康后果有关。脂肪衍生的脂肪因子在肥胖症中长期升高，并导致动脉粥样硬化、糖尿病和一些癌症的发生。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。目前尚不清楚脂肪因子是否会在生殖组织中引发炎症反应，或者这种反应是否会导致肥胖者生育力下降、流产增加和其他不利的生殖后果。使用饮食诱导肥胖的小鼠模型，我们将检验肥胖会在生殖组织中产生免疫缺陷，从而导致不利的生殖结果的假设。许多脂肪因子mRNAs的半衰期很短，它们的表达受影响其稳定性的mRNA结合蛋白的调节。锌指蛋白-36(ZFP36)是一种mRNA结合蛋白，能破坏靶mRNAs的稳定性，导致信息破坏和蛋白表达减弱。已知ZFP36可以抑制重要因子的表达，包括肿瘤坏死因子(TNF)-1、单核细胞趋化蛋白(MCP)-1、白细胞介素6(IL)-6和血管内皮生长因子(VEGF)。在脂肪细胞中，ZFP36的信使核糖核酸靶点很少。我们假设：1)与肥胖相关的慢性炎症直接影响子宫内膜和卵巢组织，促进局部炎症反应，损害生育能力，并导致不良妊娠结局；2)脂肪细胞表达的ZFP36抑制脂肪库中的炎症。我们的目标是确定ZFP 36的分子靶点，并在体外脂肪细胞和饮食诱导肥胖的小鼠模型中测试ZFP 36的生物学功能。利用靶向基因敲除和靶向过表达的方法，我们的模型系统将被用于更好地了解脂肪组织的炎症环境及其对生殖组织的内分泌/旁分泌影响。我们将测试增强ZFP36在脂肪细胞中的表达是否可以抑制局部和全身炎症，并缓解肥胖小鼠不良生殖结局的发展。这项建议侧重于一种新的机制，通过靶向脂肪细胞中脂肪因子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，用于治疗由肥胖和炎症调节的重要医疗条件，包括动脉粥样硬化、糖尿病和损害母亲和婴儿的不良生殖结果。

DESCRIPTION (provided by applicant): Obesity produces a systemic inflammatory state associated with adverse health outcomes. Fat-derived adipokines are chronically elevated in obesity and contribute to the development of atherosclerosis, diabetes, and some cancers. Adipokines exert local effects on adipose tissue physiology and unfavorable systemic effects on liver, lung, muscle, and the vasculature. It is not known whether adipokines provoke an inflammatory response in reproductive tissues or if such a response contributes to decreased fertility, increased miscarriages, and other adverse reproductive outcomes in obese individuals. Using a mouse model of diet- induced obesity, we will test the hypothesis that obesity produces immune defects in reproductive tissues that lead to adverse reproductive outcomes. Many adipokine mRNAs have a short half-life and their expression is modulated by mRNA-binding proteins that influence their stability. Zinc Finger Protein-36 (ZFP36) is an mRNA- binding protein that destabilizes target mRNAs leading to message destruction and diminished protein expression. ZFP36 is known to repress expression of important factors including Tumor Necrosis Factor (TNF)-1, Monocyte Chemotactic Protein (MCP)-1, Interleukin (IL)-6, and Vascular Endothelial Growth Factor (VEGF). Few mRNA targets of ZFP36 have been described in adipocytes. We hypothesize that: 1) the chronic inflammation associated with obesity has direct effects on endometrial and ovarian tissues, promotes local inflammatory responses, impairs fertility, and causes adverse pregnancy outcomes, and 2) that adipocyte-expressed ZFP36 represses inflammation in fat depots. We aim to identify the molecular targets of ZFP36 and to test the biological functions of ZFP36 in adipocytes in vitro and in a mouse model of diet-induced obesity. Using targeted gene knockdown and targeted over-expression approaches, our model systems will be employed to better understand the inflammatory environment of fat tissue and its endocrine/paracrine effects on reproductive tissues. We will test whether enhancing ZFP36 expression in adipocytes can suppress local and systemic inflammation and mitigate against the development of adverse reproductive outcomes in obese mice. This proposal focuses on a new mechanism for regulating systemic inflammatory responses by targeting adipokine mRNA stability in fat cells. Our work may identify ZFP36 as a novel therapeutic target for important medical conditions modulated by obesity and inflammation including atherosclerosis, diabetes, and adverse reproductive outcomes which harm mothers and babies.