CENTER FOR CANCER SIGNALING NETWORKS

超出提供的空间。 建议建立一个由初级和早期职业生涯主管的5个研究项目组成的COBRE 教职员工和3个研究核心设施。该中心的科学主题将是癌症信号网络， 也就是说，调控与癌症发生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。拟议中的一些重点 研究将包括DNA修复、Wnt和IGF-1信号、蛋白质组范围的蛋白质磷酸化分析、 泛素介导的蛋白分解，全球RNA聚合酶II机制，转基因小鼠模型 癌症发生，以及网络系统的生物信息学推断。正在调查的癌症将包括 肝细胞癌和卵巢滤泡癌。其中两名调查人员将从 现任科布雷(辛格博士，日特科维奇)和3名新聘用的初级教员。拟议的研究核心 是小鼠转基因、基因组学和生物信息学。前两个是从现在的中心延续下来的， 而后者将作为一个新的核心设施而建立。每个项目负责人和核心总监都有一个 指定的高级教员导师。导师由国际咨询委员会组成，该委员会由国际和平协会担任主席。选管会 评估中心运作的方方面面，并向PI和IAC提供建议。投资公司的建议也是由 布朗基因组和蛋白质组学中心指导委员会，并向 医学院和高级行政部门。该计划的目的是建立一个主题重点和 过渡到由NCI资助的PPG所需的科学素质。以下是具体目标 建议实现这些目标：目标1：研究性腺特异性转录的作用 辅活化子TAF4b在卵巢颗粒细胞癌发生中的作用；目的2：研究辅活化子TAF4b在卵巢颗粒细胞癌中的作用 WNT信号网络在肝细胞癌发生发展中的作用 这一途径可能对癌症治疗有用；目标3：描述和功能测试蛋白质组- 在广泛的基础上，肥大细胞和肥大细胞中受体交联触发的酪氨酸蛋白磷酸化的级联 通过IGF-1刺激肝癌细胞；目的4：阐明IGF-1的作用机制。 Cullin 3复合体识别与癌症中发现的细胞周期异常相关的调节蛋白 并针对它们进行泛素介导的蛋白分解；目标5：发现正常 在所有细胞中发现的氧化应激水平都参与了DNA损伤的产生，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. '