The principal investigator is a Research Instructor in the Department of Neurosurgery at Stanford University. Her long term career goal is to achieve excellence in research as well as in teaching at the graduate level. The short-term research goals are to meet the aims presented in this proposal as well as to submit an R01 research grant in two years. The objective of this application is to obtain further research support and salary for the candidate for a period of three years allowing her this period of primary concentration in research and related activities without any teaching and service load at the Medical School. The candidate plans to enhance her research and academic skills by participating in a number of symposia, national meetings, career development and scientific seminars related to her research field and by interacting with a number of senior researchers at Stanford University. The scientific environment in cancer research at Stanford University promotes interdisciplinary collaborations as well as translational research, making it a great venue for the development and growth of young scientists. The department supports the salary of the principal investigator and has committed resources to her, including lab and office space, as well as access to the Facilities on Campus. The department is committed to providing 90% of her time for the development of this proposal and has long term plans for the advance of her career. Gab1, cloned by the principal investigator during her postdoctoral fellowship, is a docking protein which becomes phosphorylated after the addition of different growth factors and stresses and is involved in several phenotypes such as growth, transformation, tubulogenesis and cell survival. The scientific goal of this application is to test the hypothesis that Gab1 is differentially and specifically activated under oxidative vs. EGF stimulation. To test this she proposes: 1) To study the pattern of phosphorylation of Gab1 upon H2O2 stimulation and the role of its partners in cell survival, by mass spectrometry and survival experiments. 2) To study the localization of Gab1 with its different partners upon H2O2 stimulation and its contribution to the survival phenotype, by FRET, cell fractionation, immunofluorescence, and survival assays. 3) To study the downstream effectors of AKT regulated by Gab1 after H2O2 stimulation, through two approaches: a) by studying the already known AKT effectors, and b) a screening approach using a phosphorylated AKT substrate antibody followed by Mass Spectrometry. By understanding how Gab1 is specifically activated downstream of receptor tyrosine kinases and oxidative stress, two major pathogenic mechanisms of cancer, strategies can be designed to interfere with cancer as well as sensitizing the cells to specific oxidative related therapies. ? ? ?
