CENTER FOR CANCER SIGNALING NETWORKS

描述（由申请人提供）： 建议建立一个由初级和早期职业教师领导的5个研究项目和3个研究核心设施组成的COBRE。该中心的科学主题将是癌症信号网络，即调节与致癌有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，蛋白质磷酸化的蛋白质组范围分析，泛素介导的蛋白质水解，全球RNA聚合酶II机制，致癌的转基因小鼠模型和网络系统的生物信息学推断。正在研究的癌症包括肝细胞癌和卵巢滤泡癌。两名研究人员将继续从目前的COBRE（辛格博士，Zhitkovich），和3名新聘请的初级教师。拟议的研究核心是小鼠转基因，基因组学和生物信息学。前两个中心是从目前的中心转过来的，后一个中心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指定的高级教师导师。顾问委员会负责评估中心运作的各个方面，并向PI和IAC提供建议。PI还由布朗基因组学和蛋白质组学中心指导委员会提供建议，并向医学院院长和高级管理人员报告。该计划的目的是建立一个主题重点和过渡到由NCI资助的PPG所需的科学口径。提出以下具体目的以实现这些目标：目的1：研究性腺特异性转录共激活因子TAF 4 b在卵巢颗粒细胞癌发展中的作用;目的2：检查Wnt信号传导网络在肝细胞癌发展中的功能，并解决该途径中的靶点是否可用于癌症治疗;目的3：在蛋白质组范围内，描述并功能性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;目的4：为了阐明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的机制，目标5：发现所有细胞中正常水平的氧化应激参与产生最终导致癌症发展的DNA损伤的新机制。

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.