This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tumor-induced angiogenesis, the formation of new blood vessels from existing vasculature in response to chemical signals from a tumor, is a crucial step in cancer development and progression. Although the sequential steps involved in tumor-induced angiogenesis are well known, the interplay between the biochemical and biomechanical mechanisms (e.g., cell-cell interactions, cell-matrix interactions, and intracellular signaling pathways) and their effects on angiogenesis is largely unresolved. The focus of this research is to develop a cell-based model of tumor-induced angiogenesis that incorporates the evolving composition of the stroma and the role of cellular interactions with its major component, the extracellular matrix, in order to better understand how to manipulate these processes for therapeutic gain. Key features of the biophysical model include the following: (1) linking processes occurring on multiple time scales, (2) controlling processes at the level of the individual cell where continuous models fail, and (3) incorporating the active role of the ECM as a source of cytokines and chemokines that stimulate angiogenesis. We have developed a numerical code,ANGIO, that simulates the biophysical model, of tumor-induced angiogenesis. Using ANGIO, we will address the following key scientific questions: (1) what is the relative importance of chemotaxis and mechanical forces, such as cellular adhesion to the extracellular matrix, in endothelial cell migration, (2) how does the extracellular matrix composition and structure influence capillary sprout formation during angiogenesis, (3) how does matrix restructuring affect cell migration and vascular structure, and (4) what is the role of different VEGF isoforms and VEGF receptors in capillary guidance and formation. The results should ultimately inform and advance efforts to develop new approaches for treating cancer and other angiogenesis-dependent diseases. We request the shared memory supercomputing resources to run ANGIO, which is a serial code. Each run will be on a single processor for 10 CPU hours. For each task above, we will conduct about 1000 runs to explore the parameter ranges and to collect statistics. Hence we will requst 30,000 CPU supercomputing hours.
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