Preclinical Evaluation of Intermediate Endpoints

中间终点的临床前评估

• 批准号: 6212350
• 负责人: BAHARA A REDDY
• 金额: --
• 依托单位: INSTITUTE FOR CANCER PREVENTION
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6212350
• 关键词: Preclinical; Evaluation; Intermediate; Endpoints

The offeror will employ two different strains of mice which have been genetically engineered to be highly susceptible to colon tumor. One strain of mice will have a deletion in the APC gene, resulting in a molecular phenotype similar to human FAP. The second strain of mice of mice will have a deletion in the MSH-2 gene, resulting in a molecular pathology similar to a subset of human HNPCC. A diet comparable to that routinely eaten in the developed world, relatively high in fat and relatively low in calcium, will be employed to modulate the tumor incidence and multiplicity in these genotypically altered mice. Samples from these mice will be taken at various time points either from control animals or animals treated with curcumin, rutin, sulindac or high Calcium high vitamin D. At these various times either colonic mucosa or specific lesions will be examined for a variety of endpoints including DNA ploidy, Proliferation status, nuclear morphometry [size, shape, texture], nucleolar morphometry, cytokeratins and adhesion molecules. In the case of the colonic mucosae , prior to appearance of large discrete lesions, analysis of individual crypts for these various endpoints should be employed. Increased or decreased expression of these various markers will be compared with the final chemopreventive activity of curcumin, rutin, sulindac and high calcium to determine whether modulation of specific chemical markers is associated with long term chemopreventive activity. In addition the studies will yield the therapeutic efficacy of these high priority preventive agents in these models which closely approximate their human counterpart.

要约人将使用两种不同品种的小鼠，这些小鼠已经被 经过基因改造后对结肠肿瘤非常敏感一 小鼠品系将在APC基因中缺失，导致 分子表型与人FAP相似。第二种小鼠 小鼠将在MSH-2基因中缺失，导致分子 病理学类似于人HNPCC的子集。一种与之相当的饮食 在发达国家经常食用，脂肪含量相对较高， 钙含量相对较低，将用于调节肿瘤 这些基因型改变小鼠的发病率和多样性。样品 将在不同时间点从这些小鼠中取出 动物或用姜黄素、芦丁、舒林酸或高钙治疗的动物 高维生素D。在这些不同的时间，无论是结肠粘膜或特定的 将检查病变的各种终点，包括DNA倍性， 增殖状态、核形态测定[大小、形状、质地]， 核仁形态测定、细胞角蛋白和粘附分子。的情况下 在出现大的离散病变之前， 对这些不同终点的单个隐窝的分析应 就业。增加或减少这些不同标记物的表达将 与姜黄素，芦丁， 舒林酸和高钙，以确定是否调制的具体 化学标记物与长期化学预防活性相关。 此外，这些研究将产生这些高剂量的治疗效果。 在这些模型中， 他们的人类对手。