Sphingolipid Biology of Cancer

鞘脂类癌症生物学

• 批准号: 8349853
• 负责人: Richard Proia
• 金额: $ 48.58万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349853
• 关键词: Apoptosis; Brush Border; Cancer Biology; Catabolism; Ceramidase; Ceramides; Development; Digestion; Enzymes; Genes; Goals; Growth; Intestinal Neoplasms; Intestines; Knockout Mice; Lipids; Longevity; Malignant Neoplasms; Mus; Pathway interactions; Physiological; Process; Signal Pathway; Signaling Molecule; Small Intestines; Sphingolipids; Sphingosine; Tissues; angiogenesis; cell growth regulation

Ceramidases are key enzymes in the regulation of the cellular levels of ceramide, sphingosine, and S1P.To explore the physiological functions of ceramidases, we disrupted the gene encoding neutral ceramidase (Asah2) in mice. Asah2 null mice have a normal life span and do not show obvious abnormalities or major alterations in total ceramide levels in tissues. The Asah2-encoded neutral ceramidase is highly expressed in the small intestine along the brush border, suggesting that the neutral ceramidase may be involved in a pathway for the digestion of dietary sphingolipids. Indeed, Asah2 null mice were deficient in the intestinal degradation of ceramide. Thus, the results indicate that the Asah2-encoded neutral ceramidase is a key enzyme for the catabolism of dietary sphingolipids and regulates the levels of bioactive sphingolipid metabolites in the intestinal tract. We are currently utilizing the Asah2 null mice to determine if defective catabolism of sphingolipids alters the growth of intestinal tumors.

神经酰胺酶是调节神经酰胺、鞘氨醇和神经节苷脂细胞水平的关键酶，为了探索神经酰胺酶的生理功能，我们在小鼠中阻断了编码中性神经酰胺酶(Asah2)的基因。Asah2基因缺失的小鼠寿命正常，组织中的总神经酰胺水平没有明显的异常或重大变化。Asah2编码的中性神经酰胺酶在灌木丛边缘的小肠中高度表达，这表明中性神经酰胺酶可能参与了摄食神经鞘脂脂的消化途径。事实上，Asah2基因缺失的小鼠在神经酰胺的肠道降解方面存在缺陷。因此，这些结果表明，Asah2编码的中性神经酰胺酶是饲料中鞘脂分解代谢的关键酶，并调节肠道中具有生物活性的鞘脂代谢产物的水平。我们目前正在利用Asah2缺失的小鼠来确定神经鞘脂的分解代谢缺陷是否会改变肠道肿瘤的生长。