Regulation of Macrophages by miRNA-155 in Colon Cancer: Benefits of Quercetin

结肠癌中 miRNA-155 调节巨噬细胞：槲皮素的益处

• 批准号: 8637442
• 负责人: ELIZABETH ANGELA MURPHY
• 金额: $ 17.42万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637442
• 关键词: Address; Adipose tissue; Adoptive Transfer; Behavior; CCL2 gene; Chronic; Colon; Colon Carcinoma; Colorectal Cancer; Data; Development; Diet; Dietary Flavonoid; Dietary Intervention; Disease; Effectiveness; Epidemiologic Studies; Evaluation; Fat-Restricted Diet; Fatty acid glycerol esters; Flavonoids; Food; Goals; Immune; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intestines; Investigation; Laboratories; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Mus; Obesity; Play; Prevention; Process; Quercetin; Regulation; Reporting; Risk; Role; Severities; Signal Pathway; Source; Symptoms; Testing; Therapeutic; Tissues; Toxic effect; Translating; cancer risk; chemokine; feeding; in vivo; interest; macrophage; mouse model; preclinical study; prevent; public health relevance; tumor; tumor microenvironment; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): High-fat diet (HFD)-induced obesity increases the risk for colorectal cancer (CRC). A pathophysiological mechanism that may link obesity to CRC risk is inflammation. Adipose tissue macrophages (ATM¿s) are a primary source of inflammation; however, there has been no systematic evaluation of their regulation in HFD-enhanced CRC. miRNA-155 (miR-155) inhibits signaling pathways in M¿s that can suppress inflammation. It is upregulated during the M¿ inflammatory response and has been implicated in playing a role in the link between inflammation and cancer. However, there are no reports of a role of miR-155 in HFD-enhanced CRC. Dietary compounds are of interest given their low toxicity profiles and their ability to target inflammation; however, there is a fundamental gap in the understanding of their effectiveness and their mechanism(s) of action. The long-term goal is to develop the flavonoid quercetin as a preventative/therapeutic strategy for obesity-enhanced CRC. The objective of this investigation is to evaluate whether M¿-induced inflammation is regulated by miR-155 in obesity-enhanced CRC, and whether dietary quercetin can target this process. The central hypothesis is that regulation of M¿-induced inflammation in obesity-enhanced CRC is mediated through miR-155, which may be an important mediator of quercetin action. The rationale is that elucidating the molecular links between obesity and CRC and identifying strategies to target these actions will translate to a more effective prevention/treatment approach in HFD-enhanced CRC. This hypothesis will be tested under two specific aims: 1) Determine the role of miR-155 in the regulation of M¿-induced inflammation in HFD-enhanced CRC; 2) Evaluate whether miR-155 can be targeted by dietary quercetin in HFD-enhanced CRC. In aim 1, we will use a miR-155-/- mouse in which obesity will be induced by HFD and CRC will be induced using AOM/DSS. We will examine inflammation and M¿ behavior in adipose tissue, immune regulation and inflammation in the tumor microenvironment, as well as tumorigenesis. Further, adoptive transfer of ATM¿s from both HFD wildtype and HFD miR-155-/- donor mice to wildtype recipient mice will be performed to determine if the effects of HFD on CRC are directly mediated through ATM¿s, and moreover, if this process is regulated by miR-155. In aim 2, we will determine if quercetin feedings can decrease expression of miR-155 in ATM¿s and if this is associated with a decrease in M¿-induced inflammation and reduced tumorigenesis. Further, using miR-155-/- mice we will determine if quercetin is mediating its effects through this miRNA. We will use adoptive transfer of ATM¿s from WT and miR-155-/- mice fed quercetin to directly determine if the benefits of quercetin on inflammation in HFD-enhanced CRC are mediated through ATM¿s. The proposed investigation is significant as it addresses prevention of incidence and progression of obesity-enhanced CRC by using a dietary food component to target M¿-induced inflammation, which is thought to at the mechanistic core of this disease.

描述（由应用提供）：高脂饮食（HFD）诱导的肥胖症会增加结直肠癌（CRC）的风险。可能将肥胖与CRC风险联系起来的病理生理机制是炎症。脂肪组织巨噬细胞（ATM）是炎症的主要来源。但是，在HFD增强的CRC中没有系统的评估。 miRNA-155（miR-155）抑制可以抑制炎症的M s的信号通路。它在炎症反应过程中被上调，并且已暗示在炎症与癌症之间发挥作用。但是，没有关于MiR-155在HFD增强CRC中的作用的报道。鉴于其低毒性谱及其靶向感染的能力，饮食化合物令人感兴趣。但是，理解其有效性和作用机制存在根本的差距。长期目标是开发类黄酮槲皮素作为肥胖增强CRC的预防/治疗策略。这项投资的目的是评估肥胖增强的CRC中miR-155的M miR-155调节MRIM-155，以及饮食槲皮素是否可以针对此过程。中心假设是通过miR-155介导了肥胖增强CRC中M诱导的炎症的调节，这可能是querytin作用的重要介体。理由是阐明肥胖与CRC之间的分子联系以及确定针对这些动作的策略将转化为HFD增强CRC中更有效的预防/治疗方法。该假设将在两个具体目的下进行检验：1）确定miR-155在HFD增强CRC中M诱导的炎症调节中的作用； 2）评估MiR-155是否可以通过HFD增强CRC中的饮食槲皮素来靶向。在AIM 1中，我们将使用 MiR-155 - / - 小鼠将使用AOM/DSS诱导HFD诱导肥胖症。我们将检查肿瘤微环境中的脂肪组织，免疫调节和感染以及肿瘤发生中的注射和M¿行为。此外，将执行从HFD WildType和HFD miR-155 - / - 供体小鼠到Wildtype受体小鼠的自适应转移，以确定HFD对CRC的影响是否直接通过ATM介导，并且是否通过MIR-155调节了此过程。在AIM 2中，我们将确定槲皮素喂养是否可以降低ATM中miR -155的表达，并且这是否与M诱导的炎症减少和减少肿瘤发生有关。此外，使用miR-155 - / - 小鼠，我们将确定槲皮素是否正在通过该miRNA介导其作用。我们将使用从WT和miR-155 - / - 小鼠喂食槲皮素的自适应转移，以直接确定槲皮素对HFD增强CRC中炎症的益处是否通过ATM介导。拟议的投资非常重要，因为它通过使用饮食食品成分来靶向M？引起的炎症来预防肥胖增强CRC的发病率和进展，这被认为是该疾病的机械核心。