INFLAMMATION, OBESITY AND RISK OF COLORECTAL ADENOMAS

描述（申请人提供）：结直肠癌（Colorectal cancer， CRC）在美国和其他西方国家很常见。令人信服的证据表明，环境因素增加了结直肠癌的风险。人们普遍认为结直肠腺瘤是结直肠癌的前兆。确定有利于腺瘤形成的环境和生活方式因素对于改善监测和预防是不可或缺的。我们的研究小组发现，在正常的直肠粘膜中，较低水平的细胞凋亡和较高的BMI是腺瘤风险的有力预测因子。这种竞争性的更新将验证系统性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风险和正常结肠上皮内低凋亡的中心假设。具体目的是：(1)测量炎症、C-反应蛋白、白细胞介素-6 （IL-6）和TNFa的循环生物标志物，并检测其与腺瘤和细胞凋亡的关系。(2)测定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)检测局部TNFa和IL6的激活或表达，以验证高水平的这些局部炎症生物标志物与腺瘤风险增加或细胞凋亡低相关的假设。(4)评估结肠上皮细胞中抗凋亡转录因子NFkB和STATS的激活情况；这些因子被多种细胞因子、脂肪因子和胰岛素激活，并与结直肠肿瘤有关。研究对象将是600名符合资格标准的男性和女性患者。常规结肠镜检查前立即采集血液样本，结肠镜检查期间采集正常直肠黏膜捏活检。细胞凋亡将在活检中使用形态学光镜和caspase-3免疫组织化学检测。ELISA法检测血浆细胞因子和脂肪因子水平。实时PCR检测局部TNFa和IL6的表达。激活的NFkB和STATS的组织水平将通过电迁移转移试验来测量。这项研究是以往研究的合理延伸。该建议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，研究结果可能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.