Ontology-driven Generation and Linking of Pathway Diagrams in Stroke Pathobiology

描述(申请人提供)：中风是美国第三大致死原因和致残原因。缺血性中风的损伤是一系列事件的结果，这些事件涉及基本细胞损伤机制之间的复杂相互作用。神经保护性中风疗法的潜力是巨大的。然而，过去25年进行的神经保护试验一直是阴性的。需要新的中风神经保护方法来打破这一僵局。该项目的目标是通过开发本体驱动的方法和系统来生成、链接和创建路径图，以模拟中风病理生物学中的生物现象，从而支持神经保护性中风治疗的新方法。我们将使用以下数据作为输入数据：基因表达谱、现有的途径数据库和相关的生物医学文献。基因本体论将提供基本的参考模式来识别、分类和关联途径。我们的重点将放在内毒素预适应的分子机制上。所发现的路径将以经过整理的数据库的形式提供，该数据库遵循已建立的生物路径数据的通用交换格式。目前的途径分析工具过于依赖人工过程，无法将基因列表组织成生物途径。本提案中描述的方法将通过使用基因本体论和自动化文本处理来减少这种依赖，以(A)捕捉促进构建生物途径的基因之间的功能相似性，以及(B)开发能够融合不同/证据来源(例如，现有的途径数据库和相关的生物医学文献)的过程。这一成果将通过以下具体目标来实现。目的1.收集功能性基因组证据，了解内毒素在卒中预适应中的神经保护机制。目的2.建立一种方法和系统来确定神经保护基因在中风中的生物学作用。目的3.利用体外和体内的缺血模型来测试使用AIMS 1-2中开发的基于知识的计算工具生成的特定神经保护通路预测的有效性。

DESCRIPTION (provided by applicant): 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.