GRANULYSIN, A NOVEL CYTOLYTIC MOLECULE

颗粒溶素，一种新型溶细胞分子

• 批准号: 2887778
• 负责人: ALAN MICHAEL KRENSKY
• 金额: $ 23.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887778
• 关键词: Mycobacterium; apoptosis; cytolysis; cytotoxic T lymphocyte; electron microscopy; gene targeting; genetically modified animals; granule; laboratory mouse; lymphoma; microorganism immunology; natural killer cells; neoplasm /cancer immunology; protein localization; secretion; toxin

DESCRIPTION (Adapted from the Investigator's Abstract): Granulysin is a newly discovered cytolytic molecule co-expressed with granzymes and perforin in granules of CTL and NK cells. This molecule is expressed constitutively in NK cells but is expressed 3-5 days after activation of T cells. It is released from cytolytic granule upon stimulation via the TCR. Recombinant granulysin lyses tumor targets and bacteria, but does not lyse RBC. The purpose of this proposal is to better define the mechanism of action of granulysin, its target specificity, and expression in disease. The specific aims are as follows: (1) Characterize the mechanism of action of granulysin, including the lytic activity of truncated or mutated forms of granulysin, formation of pores in membranes, association with lipids, ability to induce apoptosis, localization in target cells, and synergy with other molecules. (2) Better define the clinical relevance of granulysin by: (a) evaluating the specificity of lysis on panels of virally infected, microbial, and tumor target cells; and (b) evaluating expression of granulysin in disease sites, focusing on infection and cancer. (3) Generate a granulysin knock-out (KO) mouse in order to confirm its functional importance in vivo and to better characterize its mechanism of action, target specificity, and role in disease. Together these studies should provide a greater understanding of granulysin function and may permit application of this information to the design of new therapies of immune-mediate diseases.

描述（改编自调查员的摘要）：颗粒素是一个 新发现的细胞溶解分子与颗粒酶和穿孔蛋白共表达 在CTL和NK细胞的颗粒中。 该分子构成表达 在NK细胞中，但在激活T细胞后3-5天表示。 这是 通过TCR刺激后，从细胞溶剂颗粒释放。 重组 颗粒状蛋白裂解肿瘤靶标和细菌，但不裂解RBC。 这 该提议的目的是更好地定义 颗粒素，其靶标特异性和疾病中的表达。 具体 目的如下：（1）表征作用机理 颗粒素，包括截短或突变形式的裂解活性 颗粒素，膜中孔的形成，与脂质相关， 能够诱导凋亡，靶细胞中定位的凋亡以及与 其他分子。 （2）更好地定义颗粒素的临床相关性： （a）评估裂解在病毒感染的面板上的特异性， 微生物和肿瘤靶细胞； （b）评估的表达 疾病部位的颗粒素，重点是感染和癌症。 （3）生成 为了确认其功能 体内的重要性并更好地描述其作用机理， 目标特异性和在疾病中的作用。 这些研究应该在一起 提供对颗粒素功能的更多了解，并可能允许 将此信息应用于新疗法的设计 免疫疾病。