My goal ultimately is to establish an independent program of research in gastrointestinal signal transduction focusing on early tumor invasion, and developing and testing novel interventional strategies using xenograft tumor models and transgenic animal models. I also hope to develop more useful, tractable, 3-D culture model systems recapitulating tumor architecture in vitro and ultimately to assay more closely how and why tumors invade, and the relationship of surrounding, non-dysplastic cells on this invasion. Although tumor invasion is multifaceted, I have chosen to focus my studies on a central signal-integrating molecule, FAK, focal adhesion kinase in this process. This proposal is designed in three phases: 1. Stress activation of FAK -- We will extend our studies on hyperosmotic stress-stimulation of FAK in fibroblasts to epithelial and cancer cells. This involves characterization of a novel FAK signaling pathway. Given the distinct cytoskeletal organization within these distinct cell types a detailed study of the role of Rho-family GTPases and their actin regulatory effectors on FAK signaling will be done. 2. We will define FAK domains required for epithelial adherens junction down regulation -- In this specific aim we will use this in vitro model to characterize which functional FAK domains are required for v-Src-mediated and EGF/HGF-stimulated E-cadherin phosphorylation, internalization and degradation, and adherens junction down-regulation. 3. We will establish which FAK domains are required and which are sufficient for tumor cell invasion and metastasis in vivo and in 3-dimensional (3-D) culture systems. Here we will directly test, using a xenograft tumor model in nude mice, whether FAK activation by various stimuli or mutations is sufficient, and which FAK domains are required, for human gastric and colorectal tumor invasion in vivo. Using the FAK molecule as a focal point, this proposal is designed to refine my signal transduction training and to extend my technical expertise to epithelial cell biology and cell-cell junction regulation, advanced cell imaging (in live cells) and to in vivo tumor invasion and metastasis. This K08 award will permit me to establish an independent publishing track record which is so critical to obtaining a future R01.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA104039-03
Application #
7111747
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$127,170
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095