Regulation of Macrophages in Obesity-Enhanced Colon Cancer:Benefits of Quercetin

简介（由申请人提供）：Angela Murphy博士于2010年9月加入南卡罗来纳大学病理学，微生物学和免疫学学系，担任助理教授。她致力于健康相关的研究事业，她在感染，炎症和癌症的补充和替代（CAM）治疗方法领域发表了40篇同行评议的期刊文章。她的长期职业目标是为扩大全球癌症辅助治疗知识做出重大贡献。这将主要包括维持一个独立的转化研究线，参与尖端技术，获得R01资金，在高影响力期刊上发表文章，在会议上发表演讲，培训学生和初级教师，技术转让和药物发现，以及参与项目项目和中心资助。她的短期目标是扩大她的研究和培训经验，为她提供工具，在这个拟议的职业发展奖项结束之前，建立一个独立的研究项目和R01资助。在拟议的研究中，Murphy博士将在肥胖增强的CRC小鼠模型中研究miRNA-155在巨噬细胞行为调节中的作用，并进一步研究膳食槲皮素是否可以靶向这一过程。虽然很明显，她有兴趣从事癌症的CAM治疗，但她目前的培训是运动生理学。因此，拟议的研究将为她提供新的培训和专业知识，使她成为一名领先的免疫学家，并拥有进行癌症CAM机制和转化研究的工具。总的来说，这些研究将使Murphy博士获得新领域的经验和专业知识，并使用新技术，这将大大提高她获得新资金的能力，从而对结直肠癌的预防产生重大影响。南卡罗来纳大学为墨菲博士的职业发展提供了良好的环境，既有成功的导师，也有可用的研究资源。Murphy博士的导师和咨询委员会成员在CAM、炎症和癌症领域的基础科学和临床研究方面都有指导初级教师的良好记录。此外，墨菲博士可获得的机构研究基础设施是特殊的，将允许成功完成拟议的调查。拟议的职业发展计划是由墨菲博士和她的导师精心设计的，是根据她的能力量身定制的。它侧重于她最需要的培训的五个主要方面，包括：1)与导师和咨询委员会成员的会议；2)科研培训；3)拨款写作；4)课程;5)手稿写作。墨菲博士还将参加各工作组；每周实验室会议；杂志俱乐部;研讨会;车间;和会议作为培训计划的一部分。这个培训计划，她的导师和研究基础设施将为她提供

DESCRIPTION (provided by applicant): Dr. Angela Murphy joined the Department of Pathology, Microbiology and Immunology at the University of South Carolina as an Assistant Professor in September 2010. She is committed to a health- related research career as evident by her 40 peer-reviewed journal articles in the area of complementary and alternative (CAM) treatment approaches to infection, inflammation and cancer. Her long-term career goal is to significantly contribute to expanding global knowledge in CAM treatments for cancer. This will largely involve sustaining an independent line of translational research, engaging in cutting edge techniques, generating R01 funding, publishing in high impact journals, presentations at meetings, training students and junior faculty, technology transfer and drug discovery, as well as involvement in program projects and center grants. Her short-term goals are to expand her research and training experiences providing her with the tools to generate an independent research program and an R01 grant before the end of this proposed career development award. In the proposed investigation, Dr. Murphy will examine the role of miRNA-155 on the regulation of macrophage behavior in a mouse model of obesity-enhanced CRC, and further, whether dietary quercetin can target this process. While it is clear that she is interested in pursuing a career in CAM treatments for cancer, her current training is in Exercise Physiology. Therefore, the proposed studies will provide her with new training and expertise that she needs to become a leading immunologist with the tools to perform mechanistic and translational research on CAM in cancer. Overall, these studies will allow Dr. Murphy to gain the experience and expertise in new areas and using new techniques that will greatly enhance her ability to generate new funding, and thus, have a significant impact on the prevention of colorectal cancer. The University of South Carolina is an outstanding environment for the career development of Dr. Murphy in both successful mentors and the research resources that are available. Dr. Murphy's mentors and Advisory Committee members have a strong record of mentoring junior faculty in both basic science and clinical research in the area of CAM, inflammation and cancer. Further, the institutional research infrastructure that is available to Dr. Murphy is exceptional and will allow for successful completion of the proposed investigation. The proposed career development plan was carefully devised by Dr. Murphy and her mentors and is tailored to her ability. It focuses on five major aspects of training that she is in most need of including, 1) Meetings with Mentors and Advisory Committee Members; 2) Research Training; 3) Grant Writing; 4) Courses; and 5) Manuscript Writing. Dr. Murphy will also participate in Working Groups; Weekly Lab Meetings; Journal Club; Seminars; Workshops; and Conferences as part of the training plan. This training plan, her mentors and the research infrastructure will provide her with the necessary skills and expertise to become a highly competent independent investigator performing multidisciplinary research on CAM in cancer. A pathophysiological mechanism that may link obesity to colorectal (CRC) risk is inflammation. Adipose tissue macrophages are a primary source of inflammation; however, there has been no systematic evaluation of their regulation in obesity-enhanced CRC. miRNA-155 inhibits signaling pathways in macrophages that can suppress inflammation. It is upregulated during the macrophage 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 miRNA-155 in obesity-enhanced CRC. Dietary compounds are of interest given their low toxicity profiles and their ability to target inflammatio; 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 macrophage-induced inflammation is regulated by miRNA-155 in obesity-enhanced CRC, and whether dietary quercetin can target this process. Further, we will begin to evaluate the clinical efficacy of miRNA-155 as a biomarker for CRC. The central hypothesis is that regulation of macrophage-induced inflammation in obesity-enhanced CRC is mediated through miRNA-155, a process that can be targeted by dietary quercetin. The rationale is that elucidating the targets of quercetin and their mechanism of action will translate to a more effective prevention/treatment approach in obesity-enhanced CRC. This hypothesis will be tested under three Specific Aims: 1) Determine the role of miRNA-155 in the regulation of macrophage-induced inflammation in obesity-enhanced CRC; 2) Evaluate whether miRNA-155 can be targeted by dietary quercetin; and 3) Determine the clinical efficacy of miRNA-155 as a biomarker for CRC. In Aim 1, we will use a miRNA-155 -/- mouse in which obesity will be induced by high fat diet (HFD) and CRC induced using AOM/DSS. We will examine inflammation and macrophage behavior in adipose tissue, immune regulation in the tumor microenvironment, and tumorigeneis. In Aim 2, we will test the hypothesis that quercetin can decrease expression of miRNA-155 in macrophages, and thus, decrease tumorigenesis in obesity-enhanced CRC. In Aim 3, we will employ a case-control design to being to determine the clinical efficacy of miRNA-155 as a biomarker for CRC, and further, assess the associations and predictive ability of miRNA-155 and advanced-stage and high-grade. 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 macrophage-induced inflammation that is thought to at the mechanistic core of this disease.