COBRE: LOUISVILLE RES FOUND INC: P3: ELUCIDATION OF THE SIGNALING MECHANISMS

COBRE：LOUISVILLE RES FOUND INC：P3：信号机制的阐明

• 批准号: 7171221
• 负责人: BRIAN W. WATTENBERG
• 金额: $ 18.11万
• 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: 2005-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7171221
• 关键词: biomedical facility; drug discovery /isolation; neoplasm /cancer chemotherapy; structural biology

DESCRIPTION (provided by applicant): The University of Louisville Molecular Targets Center of Biomedical Research Excellence application (MTCOBRE) is focused on the identification of novel molecular targets for cancer therapy using the techniques of modern structural biology. The two major objectives of this proposal are to ensure the success of junior investigators who are members of the Molecular Targets Program at the University of Louisville and to discover new approaches to the therapy of cancer. The Specific Aims of the Molecular Targets COBRE application are to: 1. Foster successful independent research careers for each of the five principal investigators leading to independent R01 grants. 2. Further build our existing core facilities which will enhance the research capability of the five principal investigators and the other members of the program. 3. Continue to develop our Molecular Targets Program as a cohesive research program which will promote collaborative research projects and increase funding opportunities. 4. Develop an internationally and nationally recognized program which will attract the very best graduate students, postdoctoral fellows and additional faculty. 5. Most importantly, make discoveries leading to new and more effective treatments for patients with cancer. The five related projects of this MT-COBRE application will address a broad spectrum of molecular targets. The specific problems being investigated are: 1) Characterization and manipulation of an inducible isoform of 6-phosphofructo-2-kinase (iPFK-2), a major controller of glucose metabolism in malignant cells. 2) Development and testing of small molecular antagonists of monocyte/macrophage migration inhibitory factor (MIF) recently found to play an important role in carcinogenesis. 3) Elucidation of the signaling mechanisms involved in the activation-dependent lipid signaling enzyme, sphingosine kinase, and its product, sphingosine-l-phosphate, in control of cell proliferation, survival and migration. 4) Use of triplex forming oligonucleotides to target Bleomycin to the Her2/neu gene. 5) A crystallographer/biologist is being recruited to study molecular interactions important in the TRAF signaling pathway. The overarching theme of this program is the use of structural biology to develop novel strategies for therapy of neoplastic disease. We believe that these five projects, along with those of the other members of the program, represent a coherent approach to the application of modern structural biology to translational cancer research.

描述（由申请人提供）： 路易斯维尔大学生物医学研究卓越应用分子靶点中心 (MTCOBRE) 致力于利用现代结构生物学技术识别癌症治疗的新型分子靶点。该提案的两个主要目标是确保路易斯维尔大学分子目标项目成员的初级研究人员的成功，并发现癌症治疗的新方法。分子靶标 COBRE 应用程序的具体目标是： 1. 为五名主要研究者的每一位培养成功的独立研究生涯，从而获得独立的 R01 资助。 2. 进一步建设现有的核心设施，提高五名主要研究者和其他项目成员的研究能力。 3. 继续将我们的分子目标计划发展为一个有凝聚力的研究计划，这将促进合作研究项目并增加资助机会。 4. 制定国际和国内认可的项目，吸引最优秀的研究生、博士后研究员和其他教师。 5. 最重要的是，做出发现，为癌症患者提供新的、更有效的治疗方法。 该 MT-COBRE 应用的五个相关项目将解决广泛的分子靶标。正在研究的具体问题是：1) 6-磷酸果糖-2-激酶 (iPFK-2) 诱导型亚型的表征和操作，它是恶性细胞中葡萄糖代谢的主要控制者。 2）最近发现单核细胞/巨噬细胞迁移抑制因子（MIF）小分子拮抗剂的开发和测试在致癌作用中发挥着重要作用。 3) 阐明参与控制细胞增殖、存活和迁移的激活依赖性脂质信号传导酶、鞘氨醇激酶及其产物、鞘氨醇-L-磷酸所涉及的信号传导机制。 4)使用三链体​​形成寡核苷酸将博莱霉素靶向Her2/neu基因。 5) 正在招募一名晶体学家/生物学家来研究 TRAF 信号通路中重要的分子相互作用。该计划的首要主题是利用结构生物学开发治疗肿瘤疾病的新策略。我们相信，这五个项目以及该计划其他成员的项目代表了将现代结构生物学应用于转化癌症研究的连贯方法。