Macrophage-lnduced Inflammation in High Fat Diet Enhanced Breast Cancer (Proj 4)

高脂肪饮食中巨噬细胞诱导的炎症会加剧乳腺癌（项目 4）

• 批准号: 8531300
• 负责人: ELIZABETH ANGELA MURPHY
• 金额: $ 19.83万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8531300
• 关键词: Address; Adipose tissue; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Behavioral; Body fat; CCL2 gene; Cell physiology; Cessation of life; Chronic; Colon Carcinoma; Development; Diet; Dietary Component; Dietary Flavonoid; Disease; Effectiveness; Electrons; Enzymes; Epidemiologic Studies; Evaluation; Family; Fatty acid glycerol esters; Flavonoids; Food; Gene Transfer Techniques; Goals; Growth; Incidence; Infiltration; Inflammation; Inflammatory; Interleukin-6; Intestines; Investigation; Knock-out; Knockout Mice; Laboratories; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mediator of activation protein; Medical; Mus; NF-kappa B; Obesity; Play; Prevention; Process; Quality of life; Quercetin; Regimen; Regulation; Relapse; Research; Risk; Role; Staging; Techniques; Testing; Toxic effect; Transgenic Mice; Translating; Tumor Necrosis Factor-alpha; Weight Gain; Woman; base; bioactive food component; breast cancer diagnosis; cancer risk; cytokine; dietary supplements; feeding; human TNF protein; in vivo; inhibitor/antagonist; innovation; interest; intervention effect; macrophage; malignant breast neoplasm; member; mouse model; non-genetic; preclinical study; prevent; public health relevance; therapeutic target; tumor progression; tumorigenesis

ABSTRACT The development of the majority of breast cancers (BrCAs) is largely influenced by non-genetic factors such as high fat diet (HFD) induced obesity. The pathophysiological mechanisms that link HFD-induced obesity to BrCA risk include inflammatory processes; adipose tissue macrophages (M-Phi-s) are primary contributors to inflammation however there has been no systematic evaluation of their specific role in HFD-enhanced BrCA. 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 in HFD-enhanced BrCA. The long-term goal is to develop the anti-inflammatory flavonoid quercetin as a clinically testable dietary regimen to delay and/or prevent HFD-enhanced BrCA. The objective in this particular investigation is to evaluate whether M-Phi-s are a target for the anti-inflammatory effects of quercetin in HFD-enhanced BrCA and to determine if these effects are mediated through sirtuin 1 (SIRT1). The central hypothesis is that the mechanism of action of quercetin on the regulation of M-Phi-induced inflammation in HFD-enhanced BrCA is mediated through SIRTL This hypothesis has been formulated on the basis of several converging lines of evidence from the applicants' laboratory. The rationale for the proposed research is that elucidating the targets of quercetin and their mechanism of action in the regulation of these targets will translate to a more effective prevention/treatment approach in HFD-enhanced BrCA. This hypothesis will be tested by pursuing three specific aims: 1) Elucidate the stage-specific effects of quercetin on inflammation in HFD-enhanced BrCA; 2) Evaluate whether M-Phi-s are a target for the anti-inflammatory effects of quercetin in HFD-enhanced BrCA; and 3) Determine whether SIRT 1 is a mediator of the effects of quercetin in the regulation of M-Phi-induced inflammation in HFD-enhanced BrCA. Under the first aim, the C3(1)SV40Tag mouse model of BrCA, that will be fed a HFD to induce obesity, will be used to determine the stage-specific effects of quercetin on inflammation and subsequent tumorigenesis and overall survival. Under the second aim, in vivo M-Phi manipulation techniques will be used such as crossing the C3(1)Tag transgenic mouse model of BrCA with a MCP-1 knockout mouse to generate a M-Phi deficient mouse model of BrCA. This will help determine the role of M-Phi-s on the benefits of quercetin in HFD-enhanced BrCA. Finally, under aim 3, SIRT1 manipulation techniques will be used to examine the role of SIRT1 as a mediator of the effects of quercetin on M-Phi-induced inflammation in HFD-enhanced BrCA. The innovation of the proposed investigation is anchored in the examination of SIRT1 as a mediator of the benefits of the bioactive dietary component quercetin in the regulation of M-Phi-induced inflammation in HFD-enhanced BrCA. The proposed investigation is significant as it addresses prevention of incidence and progression of HFD-enhanced BrCA by using a dietary food component to target inflammation that is at the mechanistic core of this disease.

抽象的 大多数乳腺癌（BRCA）的发展在很大程度上受非遗传因素（例如高脂饮食（HFD）诱发的肥胖症）的影响。将HFD引起的肥胖与BRCA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（M-PHI-S）是引起炎症的主要因素，但是没有系统地评估其在HFD增强BRCA中的特定作用。鉴于其低毒性谱及其靶向炎症的能力，饮食化合物令人感兴趣。然而，了解其有效性和对HFD增强BRCA的作用机制的理解存在根本的差距。长期的目标是开发抗炎类黄酮槲皮素作为一种临床可检验的饮食方案，以延迟和/或预防HFD增强BRCA。该特定研究的目的是评估M-PHI-S是否是槲皮素在HFD增强BRCA中的抗炎作用的靶标，并确定是否通过SIRTUIN 1（SIRT1）介导了这些作用。中心假设是，槲皮素对HFD增强BRCA调节M-PHI诱导的炎症的作用机理是通过SIRTL介导的，该假设是根据申请人实验室的几种融合证据来提出的。拟议的研究的基本原理是阐明槲皮素的靶标及其在调节这些靶标中的作用机理将转化为HFD增强BRCA的更有效的预防/治疗方法。该假设将通过追求三个具体目的来检验：1）阐明槲皮素对HFD增强BRCA炎症的特异性影响； 2）评估M-Phi-S是否是槲皮素在HFD增强BRCA中的抗炎作用的靶标； 3）确定SIRT 1是否是槲皮素在HFD增强BRCA中M-PHI诱导的炎症调节中的作用的中介。在第一个目的下，将使用HFD喂养HFD的C3（1）SV40TAG小鼠模型，以诱导肥胖症，用于确定槲皮素对炎症和随后的肿瘤发生和整体存活的特异性影响。在第二个目标下，将使用体内M-PHI操纵技术，例如将BRCA的C3（1）TAG TAG转基因小鼠模型与MCP-1基因敲除鼠标一起生成BRCA的M-PHI缺陷小鼠模型。这将有助于确定M-Phi-S对槲皮素在HFD增强BRCA中的好处的作用。最后，在AIM 3下，SIRT1操纵技术将用于检查SIRT1作为槲皮素对HFD增强BRCA中M-PHI诱导的炎症作用的介体的作用。拟议的研究的创新锚定在对SIRT1的检查中，作为在HFD增强BRCA中M-Phi诱导的炎症调节中生物活性饮食成分槲皮素的益处的中介。拟议的调查非常重要，因为它通过使用饮食食品成分来靶向该疾病机械核心的炎症来解决HFD增强BRCA的发病率和进展。