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.
Inflammation has been implicated as a link between obesity and colorectal cancer. Adipose tissue macrophages are a primary source of inflammation;however, there has been no systematic evaluation of their specific role in the progression of colorectal cancer. The overall goal of this proposal is to gain an understanding of the role and regulation of adipose tissue macrophage-induced inflammation in obesity enhanced colorectal cancer that could be targeted in future investigations using behavioral and or medical treatments.
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