CENTER FOR CANCER SIGNALING NETWORKS

癌症信号网络中心

• 批准号: 6988679
• 负责人: John M Sedivy
• 金额: $ 181.33万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988679
• 关键词: biological signal transduction; clinical research; genetic registry /resource /referral center; molecular genetics; neoplasm /cancer genetics

DESCRIPTION (provided by applicant): It is proposed to establish a COBRE comprised of 5 research projects headed by junior and early career faculty and 3 research core facilities. The scientific theme of the Center will be cancer signaling networks, namely, the molecular mechanisms by which signaling networks relevant to carcinogenesis are regulated: transcription, protein phosphorylation and protein degradation. Some of the focal points of the proposed research will be DNA repair, Wnt and IGF-1 signaling, proteome-wide analysis of protein phosphorylation, ubiquitin-mediated proteolysis, global RNA polymerase II machinery, transgenic mouse models of carcinogenesis, and bioinformatic inference of network systems. Cancers under investigation will include hepatocellular carcinoma and ovarian follicular cancer. Two of the investigators will continue from the current COBRE (Drs. Singer, Zhitkovich), and 3 are newly hired junior faculty. The proposed research core are Mouse Transgenics, Genomics, and Bioinformatics. The first two carry over from the current Center, while the latter will be established as a new core facility. Each project leader and core director has an assigned senior faculty mentor. The mentors comprise the IAC which is chaired by the PI The EAC evaluates all aspects of the Center's operation and advises the PI and the IAC. The PI is also advised by the Steering Committee of the Brown Center for Genomics and Proteomics, and reports to the Dean of the Medical School and the senior administration. The of the program is to establish both a thematic focus and the caliber of science required for a transition to a PPG funded by the NCI. The following Specific Aims are proposed to achieve these goals: Aim 1: To investigate the role of the gonad-specific transcriptional coactivator TAF4b in the development of ovarian granulosa cell cancer; Aim 2: To examine the function of Wnt signaling networks in the development of hepatocellular carcinoma and to address whether targets in this pathway may be useful for cancer therapy; Aim 3: To describe and functionally test, on a proteome-wide basis, cascades of tyrosine protein phosphorylation triggered by receptor crosslinking in mast cells and by IGF-1 stimulation in hepatocellular carcinoma cells; Aim 4: To elucidate the mechanisms by which Cullin 3 complexes recognize regulatory proteins causally connected to cell cycle aberrations found in cancer and target them for ubiquitin-mediated proteolysis; Aim 5: To discover novel mechanisms by which normal levels of oxidative stress found in all cells participate in generating DNA damage that ultimately leads to the development of cancer.

描述（由申请人提供）： 建议建立一个 COBRE，由 5 个由初级和早期职业教师领导的研究项目和 3 个研究核心设施组成。该中心的科学主题将是癌症信号网络，即与癌发生相关的信号网络受到调节的分子机制：转录、蛋白质磷酸化和蛋白质降解。拟议研究的一些重点将是 DNA 修复、Wnt 和 IGF-1 信号传导、蛋白质磷酸化的全蛋白质组分析、泛素介导的蛋白质水解、全局 RNA 聚合酶 II 机制、致癌的转基因小鼠模型以及癌症的生物信息学推断。网络系统。正在研究的癌症包括肝细胞癌和卵巢滤泡癌。其中两名研究人员将继续担任目前的 COBRE（辛格博士、日特科维奇），另外 3 名研究人员是新聘用的初级教员。拟议的研究核心是小鼠转基因、基因组学和生物信息学。前两个设施是从当前中心遗留下来的，而后者将作为一个新的核心设施建立。每个项目负责人和核心主任都有一名指定的高级导师。导师由 IAC 组成，IAC 由 PI 担任主席。EAC 评估中心运营的各个方面，并向 PI 和 IAC 提供建议。 PI 还接受布朗基因组学和蛋白质组学中心指导委员会的建议，并向医学院院长和高级管理人员报告。该计划的目的是确定过渡到 NCI 资助的 PPG 所需的主题重点和科学水平。为了实现这些目标，提出了以下具体目标： 目标 1：研究性腺特异性转录共激活因子 TAF4b 在卵巢颗粒细胞癌发展中的作用；目标 2：检查 Wnt 信号网络在肝细胞癌发生过程中的功能，并探讨该通路中的靶标是否可用于癌症治疗；目标 3：在全蛋白质组的基础上描述和功能测试由肥大细胞中的受体交联和肝细胞癌细胞中的 IGF-1 刺激触发的酪氨酸蛋白磷酸化级联；目标 4：阐明 Cullin 3 复合物识别与癌症中发现的细胞周期异常有因果关系的调节蛋白的机制，并将其作为泛素介导的蛋白水解的目标；目标 5：发现所有细胞中正常水平的氧化应激参与产生 DNA 损伤并最终导致癌症发展的新机制。