This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Biologically active sphingolipids play key roles in cancer pathogenesis. While the sphingolipid pathway itself has been extensively studied, its interaction with other genes and pathways is poorly understood but is essential for its action in cancer pathogenesis. We have developed the concept of ontology fingerprint ?a list of ontology terms overrepresented in the PubMed abstracts linked to a gene or a pathway along with their corresponding enrichment p-value, to characterize genes and pathways. We further identified genes of a pathway by comparing their ontology fingerprints ?the more similar the ontology fingerprint between a gene and a pathway, the more likely the gene will play a role in the pathway. Based on this approach, we hypothesize that: 1) genes and pathways interacting with sphingolipid pathway and influencing its role in cancer pathogenesis will share similar ontology fingerprints with sphingolipid pathway and genes;2) these genes and pathways can be identified by comparing their ontology fingerprint with that of sphingolipid pathway and genes;3) we can decipher how these genes and pathways interact with sphingolipid pathway by tracing back to the biomedical literatures contributed to their ontology fingerprints;4) the inferred relationship between genes and pathways can be investigated and validated by checking whether these genes are co-expressed in cancer cells and whether they are located in the loci strongly associated with cancer identified from genome-wide association studies. We will evaluate our hypothesis by evaluating the following specific aims: 1) Identify genes and pathways interacting with sphingolipid pathway by ontology fingerprints and Bayesian model;and 2) Analyze and validate the interplay of identified genes and pathways with sphingolipid pathway by deciphering the functional role of identified genes and pathways in cancer pathogenesis involved in sphingolipid pathway using PubMed literatures, co-expression patterns of identified genes and the association of these genes with genomic loci that are identified to be associated with cancer pathogenesis from Genome Wide Association Studies. Our long term goal is to develop computational and statistical methods to integrate information from biomedical literature, transcription profiling and genome-wide association study to study genes and pathways interacting with sphingolipid pathway and to decipher the role of such interplay in cancer pathogenesis.
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