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

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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.