INFLAMMATION, OBESITY AND RISK OF COLORECTAL ADENOMAS

描述(申请人提供)：结直肠癌(CRC)在美国和其他西方国家很常见。令人信服的证据表明，环境因素增加了CRC的风险。一般认为，结直肠腺瘤是结直肠癌的先兆。确定有利于腺瘤形成的环境和生活方式因素是改进监测和预防不可或缺的一部分。我们小组发现，正常外观的直肠粘膜中细胞凋亡水平较低和BMI增加是腺瘤风险的强烈预测因素。这种相互竞争的更新将检验中心假设，即全身细胞因子和脂肪因子或局部炎症生物标志物预测结直肠腺瘤的风险和正常结肠上皮中的低凋亡。其具体目的是：(1)检测炎症、C反应蛋白、白介素6(IL-6)和肿瘤坏死因子(TNFa)等循环生物标记物，并检测其与腺瘤和细胞凋亡的关系。(2)检测循环脂肪因子瘦素和脂联素，并检测其与腺瘤和细胞凋亡的关系。(3)检测肿瘤组织中肿瘤坏死因子α(TNFa)和白介素6(IL6)的局部活化或表达，以验证高水平的局部炎症标志物与腺瘤风险增加或低细胞凋亡率相关的假说。(4)研究抗凋亡转录因子NFkB和STATS在结肠上皮细胞中的激活情况；这些因子可被多种细胞因子、脂肪因子和胰岛素激活，并与大肠肿瘤的发生有关。研究对象将是600名符合资格标准的自愿男性和女性患者。血样将在常规结肠镜检查前立即采集，并在结肠镜检查期间采集正常直肠粘膜的夹层活检。在活检组织中将使用基于形态光学显微镜的分析和caspase-3免疫组织化学来测量细胞凋亡。用双抗体夹心法测定血浆细胞因子和脂肪因子水平。用实时定量聚合酶链式反应检测肿瘤坏死因子α和白介素6的局部表达。组织中活化的NFkB和STATS的水平将通过电迁移率变化分析来测量。这项研究是先前研究的合乎逻辑的延伸。这项建议有可能提高我们对肥胖和炎症在结直肠肿瘤发生中的作用的理解，并预测炎症和腺瘤风险之间的机制联系。最终，这些结果可能会为监测和预防战略提供参考。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is common in the United States and other Western countries. Compelling evidence indicates that environmental factors increase the risk of CRC. It is generally accepted that colorectal adenomas are precursors to CRC. Defining environmental and lifestyle factors that favor adenoma formation is integral to improved surveillance and prevention. Our group found that lower levels of apoptosis in normal appearing rectal mucosa and increased BMI were strong predictors of adenoma risk. This competing renewal will test the central hypothesis that systemic cytokines and adipokines or local biomarkers of inflammation predict risk for colorectal adenomas and low apoptosis within the normal colonic epithelium. The specific aims are: (1) To measure circulating biomarkers of inflammation, C- reactive protein, interleukin-6 (IL-6), and TNFa, and test for associations with adenomas and apoptosis. (2) To measure circulating adipokines leptin and adiponectin and test for associations with adenomas and apoptosis. (3) To assay local activation or expression of TNFa and IL6 to test the hypothesis that high levels these local biomarkers of inflammation correlate with increased adenoma risk or low apoptosis. (4) To assess activation of NFkB and STATS, anti-apoptotic transcription factors in colonic epithelial cells; these factors are activated by multiple cytokines, adipokines and insulin, and are linked to colorectal neoplasia. Study subjects will be 600 consenting male and female patients who meet eligibility criteria. Blood samples will be collected immediately before routine colonoscopy and pinch biopsies of normal rectal mucosa will be collected during colonoscopy. Apoptosis will be measured in biopsies using morphological light microscopy-based assays and caspase-3 immunohistochemistry. Plasma levels of cytokines and adipokines will be measured by ELISA. Local expression of TNFa and IL6 will be measured by real time PCR. Tissue levels of activated NFkB and STATS will be measured by electromobility shift assay. This study is a logical extension of previous research. The proposal has the potential to improve our understanding of the role of obesity and inflammation in the development of colorectal neoplasia and to predict mechanistic links between inflammation and adenoma risk. Ultimately the results may inform surveillance and prevention strategies.