Hyperproliferation of colonic crypts is recognized as an important risk factor for colon carcinogenesis. Chronic intestinal inflammation, especially of the colon, also significantly increases the risk of colon cancer. However, the complex inter-relationships between inflammation and proliferation, resulting in mucosal priming for neoplasia, are less well understood. We will employ a murine model of hyperplasia, Transmissible Murine Colonic Hyperplasia (TMCH), caused by a Gram-negative bacterium, Citrobacter rodentium (CR.) to study how hyperplasia, in the presence or absence of chronic inflammation affects epigenetic signaling via 2- catenin/NF-:B. TMCH is characterized by epithelial hyperproliferation and hyperplasia. Depending upon the genetic background, varying degrees of inflammation occur with pathophysiological similarities to human inflammatory gastrointestinal diseases. In Swiss-Webster outbred mice, TMCH is associated with increases in 2-catenin and its downstream targets (cyclin D1 and c-myc) that precede changes in NF-:B activity. Dietary pectin (6%, source of butyrate) blocks increases in 2-catenin levels and NF-:B activity and significantly abrogates hyperplasia. Intriguingly, blocking NF-:B activation alone via proteasomal inhibition of I:B1 does not reduce hyperplasia. In genetically susceptible C3H/HeNHsd (C3H) inbred mice, an initial phase of hyperplasia is followed by chronic inflammation in response to CR infection, accompanied by dramatic increases in the presence of intra-epithelial CD3+/CD103+T cells and several pro-inflammatory agents (such as IL-12, IL-6, KC etc). Based on these findings, our hypotheses are: 1) Epigenetic alterations in the relative levels of activated 2-catenin and NF-:B will be different in the presence or absence of inflammation;2) The relative inhibitory efficacy of pectin will be dictated by the epigenetic alterations and associated inflammation. These hypotheses will be tested in Aims 1 and 2. The mechanisms leading towards elevated abundance and activation of 2-catenin in the TMCH model remains unknown.
In Aim 3, we wil examine some of these mechanisms by utilizing both in vivo and in vitro approaches. These experiments will allow us to learn for the first time if epigenetic alterations in 2-catenin and NF-:B in presence or absence of inflammation, impact the relative inhibitory efficacy of dietary pectin on hyperplasia and how dietary intervention affects mucosal priming for neoplasia. Increased rates of proliferation form the earliest and, most probably, the necessary background for the transformation of a normal colonic epithelium to cancer. Chronic intestinal inflammation, especially of the colon, also significantly increases risk of developing cancer. However, the complex inter-relationships among inflammation and proliferation leading subsequently to mucosal priming for neoplasia, is less well understood. Utilizing a mouse model of hyperproliferation and hyperplasia, TMCH (transmissible murine colonic hyperplasia) we will study how epigenetic alterations in 2- catenin and NF-:B in the presence or absence of inflammation, impact the relative inhibitory efficacy of dietary pectin on hyperplasia and how dietary intervention affects mucosal priming for neoplasia.
Increased rates of proliferation form the earliest and, most probably, the necessary background for the transformation of a normal colonic epithelium to cancer. Chronic intestinal inflammation, especially of the colon, also significantly increases risk of developing cancer. However, the complex inter-relationships among inflammation and proliferation leading subsequently to mucosal priming for neoplasia, is less well understood. Utilizing a mouse model of hyperproliferation and hyperplasia, TMCH (transmissible murine colonic hyperplasia) we will study how epigenetic alterations in ?-catenin and NF-?B in the presence or absence of inflammation, impact the relative inhibitory efficacy of dietary pectin on hyperplasia and how dietary intervention affects mucosal priming for neoplasia.
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