EXCEED THE SPACE PROVIDED.It is proposed to establish a COBRE comprised of 5 research projects headed by junior and early careerfaculty 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 proposedresearch 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 ofcarcinogenesis, and bioinformatic inference of network systems. Cancers under investigation will includehepatocellular carcinoma and ovarian follicular cancer. Two of the investigators will continue from thecurrent COBRE (Drs. Singer, Zhitkovich), and 3 are newly hired junior faculty. The proposed research coreare 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 anassigned senior faculty mentor. The mentors comprise the IAC which is chaired by the PI. The EACevaluates all aspects of the Center's operation and advises the PI and the IAC. The PI is also advised by theSteering Committee of the Brown Center for Genomics and Proteomics, and reports to the Dean of theMedical School and the senior administration. The of the program is to establish both a thematic focus andthe caliber of science required for a transition to a PPG funded by the NCI. The following Specific Aims areproposed to achieve these goals:
Aim 1 : To investigate the role of the gonad-specific transcriptionalcoactivator TAF4b in the development of ovarian granulosa cell cancer;
Aim 2 : To examine the function ofWnt signaling networks in the development of hepatocellular carcinoma and to address whether targets inthis 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 andby IGF-1stimulation in hepatocellular carcinoma cells;
Aim 4 : To elucidate the mechanisms by whichCullin 3 complexes recognize regulatory proteins causally connected to cell cycle aberrations found in cancerand target them for ubiquitin-mediatedproteolysis;
Aim 5 : To discover novel mechanisms by which normallevels of oxidative stress found in all cells participate in generating DNA damage that ultimately leads to thedevelopment of cancer. '
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