Stroke is the third leading cause of death and the leading cause of disability in the United States. Injury due to ischemic stroke occurs as a result of a sequence of events that involve complex interactions between fundamental cell injury mechanisms. The potential for neuroprotective stroke therapy is enormous. However, neuroprotective trials run over the past 25 years have been negative. New approaches to stroke neuroprotection are needed to break this impasse. The goal of this project is to support new approaches to neuroprotective stroke therapy by developing an ontology-driven methodology and system for generating, linking, and creating pathway diagrams that model biological phenomena in stroke pathobiology. We will use the following as input data: gene expression profiles, existing pathway databases, and relevant biomedical literature. The Gene Ontology will provide basic reference schema to identify, classify, and relate pathways. Our focus will be on the molecular mechanisms involved in Lipopolysaccharide preconditioning. The pathways discovered will be made available in the form of a curated database that adheres to established common exchange formats for biological pathway data. Current pathway analysis tools are too dependent on manual processes to organize gene lists into biological pathways. The approach described in this proposal will reduce such a dependency by using the Gene Ontology and automated text processing to (a) capture functional similarities among genes that facilitate the construction of biological pathways, and (b) develop processes that enable the fusion of diverse / sources of evidence (e.g., existing pathway databases and relevant biomedical literature). This achievement will be carried out through the following specific aims.
Aim 1. Gather functional genomic evidence for neuroprotective mechanisms that underlie LPS preconditioning in stroke.
Aim 2. Develop a method and a system to define the biological role of neuroprotective genes in stroke.
Aim 3. Utilize in vitro and in vivo models of ischemia to test the validity of specific neuroprotective pathway predictions generated using knowledge-based computational tools developed in Aims 1-2.
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