CENTER FOR CANCER SIGNALING NETWORKS

超出所提供的空间。 建议建立一个由5个研究项目组成的COBRE，由初级和初级职业领导 三个研究中心和三个研究中心。该中心的科学主题将是癌症信号网络， 即，调节与致癌相关的信号网络的分子机制： 转录、蛋白质磷酸化和蛋白质降解。拟议的《公约》的一些协调中心 研究将是DNA修复，Wnt和IGF-1信号，蛋白质磷酸化的蛋白质组分析， 泛素介导的蛋白水解，全局RNA聚合酶II机制，转基因小鼠模型， 致癌作用和网络系统的生物信息学推断。正在研究的癌症将包括 肝细胞癌和卵巢滤泡癌。两名调查人员将继续从 现任COBRE（Singer，Zhitkovich博士），3名新聘初级教员。拟议的研究核心 是小鼠转基因、基因组学和生物信息学。前两个从当前中心结转， 而后者将作为一个新的核心设施。每个项目负责人和核心主任都有一个 被指派为高级教师导师这些导师组成由首席研究员担任主席的独立咨询委员会。选管会 评估中心运作的各个方面，并向PI和IAC提供建议。PI也由 布朗基因组学和蛋白质组学中心的指导委员会，并向该中心的院长报告。 医学院和高级管理人员。该方案的目的是建立一个主题重点， 向国家癌症研究所资助的PPG过渡所需的科学水平。以下具体目标是 目的1：研究性腺特异性转录因子在性腺发育中的作用， 共激活因子TAF 4 b在卵巢颗粒细胞癌发生发展中的作用;目的2：研究TAF 4 b在卵巢颗粒细胞癌发生发展中的作用。 Wnt信号网络在肝细胞癌发生发展中的作用及靶点探讨 目的3：在蛋白质组上描述和功能测试， 广泛的基础，酪氨酸蛋白磷酸化级联反应由肥大细胞中的受体交联触发， 目的4：阐明IGF-1刺激肝癌细胞增殖的机制， Cullin 3复合物识别与癌症中发现的细胞周期畸变有因果关系的调节蛋白 并靶向它们进行泛素介导的蛋白质水解;目的5：发现正常的 在所有细胞中发现的氧化应激水平参与产生DNA损伤，最终导致 癌症的发展。'

EXCEED THE SPACE PROVIDED. 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 phosphorylationtriggered by receptor crosslinking in mast cells and by IGF-1stimulation 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-mediatedproteolysis; 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. '