Sphingosine Kinase Compartmentalization in Tumorogenesis

肿瘤发生中的鞘氨醇激酶区室化

• 批准号: 7095132
• 负责人: BRIAN W. WATTENBERG
• 金额: $ 25.31万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095132
• 关键词: 3T3 cells; active sites; biological signal transduction; carcinogenesis; cell membrane; cell proliferation; cell transformation; chloride channels; confocal scanning microscopy; density gradient ultracentrifugation; enzyme activity; immunofluorescence technique; molecular oncology; neoplasm /cancer therapy; phosphorylation; protein kinase; protein localization; second messengers; sphingosine; tumor suppressor proteins; western blottings

DESCRIPTION (provided by applicant): The long-range goal of the proposed research is to identify molecular targets in sphingolipid signaling pathways for the development of therapeutics to treat cancer. The focus of the present proposal is the signaling enzyme sphingosine kinase-1, which produces the potent second messenger, sphingosine-1-phosphate. Sphingosine kinase represents a candidate target for cancer therapy. This concept is based on the observations that sphingosine kinase is overexpressed in many tumors and that experimental overproduction of sphingosine kinase transforms cells from a growth-controlled state to a tumorigenic state. The localization of sphingosine kinase to distinct intracellular sites is key to its ability to transform cells. The proposed experimental plan will determine why localization is important for transformation. This will form the basis for a discovery of novel molecular targets involved in the transforming ability of sphingosine kinase. To accomplish this goal, three specific aims are proposed. Specific Aim 1. Determine the activation-dependent subcellular localization of sphingosine kinase and sphingolipid metabolites affected by SK activity. Specific Aim 2. Determine the role of SK localization in cellular transformation and protumorigenic pathways. Specific Aim 3. The plasma membrane sphingosine-1-phosphate transport mechanism. Determine the mechanism and functional effects of enhanced sphingosine-1-phosphate secretion by activation of hSK-1.

描述（由申请人提供）：拟议研究的长期目标是确定鞘脂信号通路中的分子靶点，以开发治疗癌症的疗法。目前建议的重点是信号酶鞘氨醇激酶-1，它产生有效的第二信使，鞘氨醇-1-磷酸。鞘氨醇激酶代表癌症治疗的候选靶标。这一概念是基于以下观察结果：鞘氨醇激酶在许多肿瘤中过表达，并且鞘氨醇激酶的实验性过度产生将细胞从生长控制状态转变为致瘤状态。鞘氨醇激酶定位于不同的细胞内位点是其转化细胞能力的关键。拟议的实验计划将确定为什么本地化对转化很重要。这将为发现参与鞘氨醇激酶转化能力的新分子靶点奠定基础。为实现这一目标，提出了三个具体目标。具体目标1.确定受SK活性影响的鞘氨醇激酶和鞘脂代谢产物的活化依赖性亚细胞定位。具体目标2。确定SK定位在细胞转化和促肿瘤发生途径中的作用。具体目标3。质膜鞘氨醇-1-磷酸转运机制。确定通过激活hSK-1增强1-磷酸鞘氨醇分泌的机制和功能效应。