INFLAMMATION, OBESITY AND RISK OF COLORECTAL ADENOMAS

描述（由申请人提供）：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，环境因素会增加CRC的风险。一般认为结直肠腺瘤是CRC的前体。确定有利于腺瘤形成的环境和生活方式因素是改善监测和预防不可或缺的。我们的研究小组发现，正常直肠粘膜细胞凋亡水平较低和BMI增加是腺瘤风险的强预测因子。这种竞争性更新将检验中心假设，即系统性细胞因子和脂肪因子或炎症的局部生物标志物预测结直肠腺瘤的风险和正常结肠上皮内的低凋亡。具体目标是：（1）测量炎症的循环生物标志物、C-反应蛋白、白细胞介素-6（IL-6）和TNFa，并测试与腺瘤和凋亡的关联。(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)测定TNFa和IL 6的局部活化或表达，以检验高水平的这些炎症局部生物标志物与腺瘤风险增加或低凋亡相关的假设。(4)为了评估NFkB和STATS的激活，结肠上皮细胞中的抗凋亡转录因子;这些因子被多种细胞因子、脂肪因子和胰岛素激活，并与结直肠肿瘤相关。研究受试者为600例符合合格性标准的知情同意男性和女性患者。将在常规结肠镜检查前即刻采集血样，并在结肠镜检查期间采集正常直肠粘膜的捏取活检。将使用基于形态学光学显微镜的测定和半胱天冬酶-3免疫组织化学在活检中测量细胞凋亡。将通过ELISA测量细胞因子和脂肪因子的血浆水平。通过真实的时间PCR测量TNF α和IL 6的局部表达。将通过电迁移率变化测定法测量活化的NFkB和STATS的组织水平。本研究是对以往研究的逻辑延伸。该提案有可能提高我们对肥胖和炎症在结直肠肿瘤发展中的作用的理解，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信息。

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.