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: 8606955
• 负责人: CALEB BENJAMIN KALLEN
• 金额: $ 25.69万
• 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/8606955
• 关键词: anti; inflammatory; mRNA; binding; protein

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.

描述（由申请人提供）：肥胖产生与不良健康结果相关的全身炎症状态。脂肪源性脂肪因子在肥胖症中长期升高，并促进动脉粥样硬化、糖尿病和某些癌症的发展。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。目前尚不清楚脂肪因子是否会引起生殖组织的炎症反应，或者这种反应是否会导致肥胖个体的生育力下降，流产增加和其他不良生殖结果。使用饮食诱导肥胖的小鼠模型，我们将检验肥胖在生殖组织中产生免疫缺陷导致不良生殖结果的假设。许多脂肪因子mRNA具有短的半衰期，并且它们的表达受到影响其稳定性的mRNA结合蛋白的调节。锌指蛋白-36（ZFP 36）是一种mRNA结合蛋白，其使靶mRNA不稳定，导致信息破坏和蛋白质表达减少。已知ZFP 36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（IL）-6和血管内皮生长因子（VEGF）。已经在脂肪细胞中描述了ZFP 36的几个mRNA靶标。我们假设：1）与肥胖相关的慢性炎症对子宫内膜和卵巢组织具有直接影响，促进局部炎症反应，损害生育能力，并导致不良妊娠结果，以及2）脂肪细胞表达的ZFP 36抑制脂肪库中的炎症。我们的目的是确定ZFP 36的分子靶点，并在体外脂肪细胞和饮食诱导的肥胖小鼠模型中测试ZFP 36的生物学功能。使用靶向基因敲除和靶向过表达方法，我们的模型系统将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。我们将测试在脂肪细胞中增强ZFP 36表达是否可以抑制局部和全身炎症，并减轻肥胖小鼠不良生殖结果的发展。该提案的重点是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的新机制。我们的工作可能将ZFP 36确定为一种新的治疗靶点，用于治疗由肥胖和炎症调节的重要疾病，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。