LIPID SIGNALLING TARGETS

脂质信号靶点

• 批准号: 6300371
• 负责人: GARTH POWIS
• 金额: $ 16.56万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300371
• 关键词: antineoplastics; bioassay; biological products; biological signal transduction; chemical fingerprinting; chemical kinetics; combinatorial chemistry; cooperative study; drug screening /evaluation; enzyme activity; enzyme inhibitors; enzyme mechanism; growth inhibitors; human tissue; lipid metabolism; medicinal plants; microorganism culture; molecular cloning; neoplastic transformation; phospholipase C; phospholipase D; phospholipase inhibitor; phospholipids; plant extracts; protein purification

Traditional approaches to cancer drug development have failed to identify anticancer drugs that have a significant therapeutic benefit for most cancer patients. New approaches to cancer drug development are clearly needed. Recent information suggests that cancer can be considered a disease of deranged intracellular signalling. We will use cancer cell- specific intracellular signalling targets and screen diverse natural product extracts as sources of novel chemical structures to provide specific inhibitors of the targets as potential drugs for the prevention and treatment of cancer. In this project we will focus our work on phospholipid metabolism that occurs as a major early event in signalling by a number of oncogenes important to human cancer. The enzymes of phospholipid metabolism, thus, offer attractive surrogate targets for the inhibition of oncogene signalling. The targets we will study initially are: phosphatidylinositol specific phospholipase C, phosphatidylinositol- 3-kinase and phospholipase D. We will conduct mechanistic studies of these signalling targets using molecular and cellular biology techniques to further define their roles in cell growth and transformation. We will screen natural product extracts from Chinese traditional and other medicinal plants, bacterial and fungal fermentation products and natural product-based combinatorial libraries, to identify novel inhibitors of these signalling targets. We will use the inhibitors we identify to modulate the activity of these targets in experimental systems and relate inhibition of the target to inhibition of cell growth and in vivo antitumor activity. The goal of our studies is to identify and develop novel natural product inhibitors of oncogene signalling pathways for the effective prevention and treatment of cancer.

传统的癌症药物开发方法未能确定 对大多数人具有显着治疗效果的抗癌药物 癌症患者。癌症药物开发的新方法显然是 需要。最近的信息表明，癌症可以被认为是一种 细胞内信号传导紊乱疾病。我们将使用癌细胞- 特定的细胞内信号传导目标并筛选多种天然 产品提取物作为新颖化学结构的来源，以提供 目标的特异性抑制剂作为潜在的预防药物 和癌症的治疗。 在这个项目中，我们的工作重点是 磷脂代谢作为信号传导的主要早期事件发生 由许多对人类癌症很重要的癌基因引起。 酶的 因此，磷脂代谢为 抑制癌基因信号传导。 我们首先要研究的目标 是：磷脂酰肌醇特异性磷脂酶C、磷脂酰肌醇- 3-激酶和磷脂酶D。我们将进行机制研究 使用分子和细胞生物学技术这些信号传导目标 进一步明确它们在细胞生长和转化中的作用。 我们将 筛选中药及其他天然产物提取物 药用植物、细菌和真菌发酵产品以及天然 基于产品的组合文库，以确定新型抑制剂 这些信号目标。我们将使用我们确定的抑制剂 在实验系统中调节这些目标的活动并关联 抑制靶标以抑制细胞生长和体内 抗肿瘤活性。 我们研究的目标是识别和发展 致癌基因信号通路的新型天然产物抑制剂 有效预防和治疗癌症。