Macrophages in High Fat Diet Enhanced Colorectal Cancer: Regulation by miRNA-155

高脂肪饮食中的巨噬细胞增强结直肠癌：miRNA-155 的调节

• 批准号: 8512253
• 负责人: ELIZABETH ANGELA MURPHY
• 金额: $ 17.88万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512253
• 关键词: Address; Adipose tissue; Adoptive Transfer; Behavioral; CCL2 gene; Calories; Chronic; Colon; Colon Carcinoma; Colorectal Cancer; Cytokine Inducible SH2-Containing Protein; Data; Development; Diet; Disease; Evaluation; Fatty acid glycerol esters; Functional RNA; Future; Goals; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intestines; Investigation; Laboratories; Link; Malignant Neoplasms; Mediating; Medical; MicroRNAs; Mus; Obesity; Play; Prevention; Process; Regulation; Reporting; Research; Risk; Role; Signal Pathway; Source; Testing; Tissues; Translating; cancer risk; chemokine; feeding; in vivo; innovation; macrophage; mouse model; non-genetic; public health relevance; saturated fat; therapeutic target; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The development of the majority of colorectal cancers (CRCs) is largely influenced by non-genetic factors such as high fat diet (HFD)-induced obesity. The pathophysiological mechanisms that link obesity to CRC risk include inflammatory processes; adipose tissue macrophages (ATM¿s) are a primary source of inflammation, however, there has been no systematic evaluation of their specific role in CRC. There is evidence to confirm a regulatory role of miRNA-155 on M¿-induced inflammation; it has been shown that miRNA-155 directly inhibits suppressor of cytokine signaling 1 (SOCS1) in M¿s, thus increasing their inflammatory potential. While it is clear that miRNA-155 can positively regulate M¿-induced inflammation, there is a fundamental gap in the understanding of its role on the regulation of ATM¿-induced inflammation in HFD enhanced CRC. The long- term goal is to understand the role of ATM¿s in HFD enhanced CRC that could be targeted using behavioral and or medical treatments. The objective of this particular investigation is to determine the role of ATM¿s on inflammation and subsequent progression of HFD enhanced CRC, and further, to evaluate if this process is regulated by miRNA-155. The central hypothesis is that the regulation of ATM¿-induced inflammation in HFD- enhanced CRC is mediated through miRNA-155. The rationale for the proposed research is that elucidating the link between obesity and CRC will translate to a more effective prevention/treatment approach. This hypothesis will be tested by pursuing two specific aims: 1) Determine the role of ATM¿s on inflammation and subsequent progression of CRC; and 2) Evaluate the role of miRNA-155 on regulation of ATM¿-induced inflammation in CRC. Under the first aim we will compare the effects of three HFDs (40% of total calories) differing in the percentage of saturated fat (6%, 12% & 24% of total calories) on CRC progression in the AOM/DSS mouse model of CRC, and further, examine the association between CRC, adipose tissue inflammation, M¿ polarization, and expression of miRNA-155. Further, using adoptive transfer of ATM¿s from mice fed HFDs to CRC mice fed normal diets (ND) we will directly determine the role of ATM¿s on progression of CRC. In the second aim, we will test the hypothesis that miRNA-155 plays a critical role in the regulation of M¿-induced inflammation in HFD enhanced CRC. To this end, using a miRNA-155-/- mouse and AOM/DSS to initiate CRC we will examine the role of miRNA-155 on ATM¿-induced inflammation and subsequent tumorigenesis. Further, using adoptive transfer of ATM¿s from HFD miRNA-155-/- mice to wildtype CRC mice that will be fed a ND we will determine if the effects of ATM¿s on CRC progression are mediated through miRNA-155. The innovation of this investigation is anchored in the examination of the role of ATM¿s in CRC, and further, the regulation of these M¿s by miRNA-155. The proposed investigation is significant as it addresses prevention of incidence and progression of HFD-enhanced CRC. If this hypothesis is correct miRNA-155 may be an important therapeutic target of ATM¿-induced inflammation in HFD-enhanced CRC.

描述（应用程序提供）：大多数有色癌症（CRC）的发展在很大程度上受非遗传因素（例如高脂饮食（HFD）引起的肥胖症）的影响。将肥胖与CRC风险联系起来的病理生理机制包括炎症过程；脂肪组织巨噬细胞（ATM）是炎症的主要来源，但是，没有系统地评估其在CRC中的特定作用。有证据可以证实miRNA -155在M诱导的炎症中的调节作用。已经表明，miRNA-155直接抑制M s中细胞因子信号1（SOCS1）的抑制，从而增加了其炎症潜力。虽然很明显，miRNA -155可以积极调节M诱导的炎症，但了解其在调节ATM诱导的HFD炎症HFD增强CRC中的作用方面存在基本差距。长期目标是了解ATM在HFD增强的CRC中的作用，该CRC可以使用行为和 /或医疗治疗。该特定研究的目的是确定ATM在HFD增强CRC的炎症和随后进展中的作用，并进一步评估该过程是否受miRNA-155的调节。中心假设是，通过miRNA-155介导了ATM？诱导的HFD增强CRC炎症。拟议研究的理由是阐明肥胖与CRC之间的联系将转化为更有效的预防/治疗方法。该假设将通过追求两个具体目的来检验：1）确定ATM在CRC炎症和随后进展中的作用； 2）评估miRNA -155在CRC中诱导的ATM诱导的炎症调节的作用。在第一个目标下，我们将比较三个HFD（占总卡路里的40％）的影响，饱和脂肪百分比（6％，12％和24％的总卡路里）对CRC的AOM/DSS小鼠模型中CRC进展的影响，并进一步研究CRC，ADipose Tispue Issigection，M€Polarlization，M€polarsization of mirna-155。此外，利用从喂养HFD的小鼠到喂养正常饮食（ND）的CRC小鼠的ATMS的自适应转移，我们将直接确定ATM在CRC进展中的作用。在第二个目的中，我们将检验以下假设：miRNA -155在调节HFD增强CRC中诱导的炎症中起关键作用。为此，使用miRNA-155 - / - 小鼠和AOM/DSS启动CRC，我们将检查miRNA-155在ATM诱导的炎症和随后的肿瘤发生中的作用。此外，利用从HFD miRNA-155 - / - 小鼠到将喂食的Wildtype CRC小鼠的自适应转移，我们将确定AMT对CRC进展的影响是否通过miRNA-155介导。这项投资的创新是基于检查ATM在CRC中的作用的基础，此外，MiRNA-155对这些M的调节。拟议的调查非常重要，因为它解决了预防HFD增强CRC的发病率和进展。如果该假设是正确的miRNA-155，则可能是ATM诱导的HFD增强CRC炎症的重要治疗靶点。