DIETARY SPHINGOLIPIDS AND PREVENTION OF COLON CANCER

膳食鞘脂与预防结肠癌

• 批准号: 2102623
• 负责人: ALFRED Harrison MERRILL
• 金额: $ 20.57万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-15 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2102623
• 关键词: biological signal transduction; cancer prevention; carcinogenesis inhibitor; cell growth regulation; ceramides; chemical carcinogenesis; chemical structure function; chemical synthesis; colon neoplasms; diet; dietary lipid; digestion; laboratory mouse; pharmacokinetics; sphingolipids; sphingosine; transcription factor

DESCRIPTION: (Adapted from Applicant's Description) The lipid backbones (sphingosine and ceramides) of complex sphingolipids have surfaced as highly bioactive compounds, modulating the activities of cellular protein kinases and phosphatases, and other enzymes involved in signal transduction pathways that regulate cell growth, differentiation, and transformation. For example, sphingosine reduces C3H/10T1/2 cell transformation in response to gamma irradiation and PMA, sphingosine enhances the differentiation of HL-60 cells, and sphingosine and some of its metabolites inhibit transformed cell growth and metastasis. Sphingolipids are prevalent in foods and ingested sphingolipids are hydrolyzed to sphingosine and caramide; therefore, they have the potential to be important inhibitors of carcinogenesis. To test this hypothesis, they have conducted preliminary studies of the effects of dietary sphingomyelin on the susceptibility of the colon to chemically induced cancer. In these studies, sphingomyelin was purified from milk and fed at up to 0.1 percent of the diet to mice exhibited aberrant crypts in colonic mucosa, but the number was significantly decreased in mice fed sphingomyelin. At the end of 52 weeks, mice fed sphingomyelin had a 20 percent incidence of colon tumors compared to 47 percent for the control group; therefore, it appears highly likely that dietary sphingolipids inhibit colon carcinogenesis. The goal of this application is to characterize this inhibition on a more molecular level, and to gain further insight into the digestion of sphingolipids. Crucial to this application is the applicant's ability to prepare chemically defined sphingolipids because naturally occurring sphingolipids are complex mixtures, and may have contaminants that could lead to misleading results. Therefore, they will synthesize N-palmitoyl-D-erythro-sphingosine and the corresponding sphingomyelin and analyze their digestion and fate in the GI tract of mice, as well as their inhibition of DMH-induced colon carcinogenesis. These investigators will provide fundamental information about the nutritional significance of dietary sphingolipids.

描述：(改编自申请人的描述)脂类 复合鞘磷脂的脊椎(鞘氨醇和神经酰胺)有 作为高度生物活性的化合物浮出水面，调节 细胞蛋白激酶和磷酸酶，以及其他涉及的酶 在调节细胞生长的信号转导通路中， 分化，转型。例如，鞘氨醇 减少C3H/10T1/2细胞对伽马的转化 放射和PMA、鞘氨醇促进HL-60细胞分化 细胞，鞘氨醇及其部分代谢物抑制转化 细胞生长和转移。神经鞘脂脂普遍存在于食品和 摄取的鞘磷脂被水解成鞘氨醇和卡胺； 因此，它们有可能成为重要的抑制因子。 致癌。为了验证这一假设，他们进行了初步的 膳食中神经鞘磷脂对多发性硬化症易感性影响的研究 从结肠癌到化学诱导癌。在这些研究中，鞘磷脂 是从牛奶中提纯出来的，并以高达0.1%的饲料喂养小鼠 结肠粘膜可见异常隐窝，但数目较少 在喂食神经鞘磷脂的小鼠中显著降低。在52年底 几周后，喂食鞘磷脂的小鼠有20%的结肠癌发病率 相比之下，对照组为47%；因此，似乎 饮食中的鞘脂极有可能抑制结肠癌的发生。 这个应用程序的目标是描述 更多的分子水平，并进一步了解消化 神经鞘脂类。对这份申请至关重要的是申请人的 能够制备化学定义的鞘磷脂，因为自然地 出现的鞘脂是复杂的混合物，可能含有污染物。 这可能会导致误导性的结果。因此，它们会合成 N-棕榈酰-D-红血鞘氨醇及其相应的鞘磷脂 并分析它们在小鼠胃肠道中的消化和去向 因为它们能抑制DMH诱导的结肠癌的发生。这些 调查人员将提供有关营养成分的基本信息 膳食神经鞘脂脂的意义。