UC Riverside

This dissertation is about the development of gene expression signature (GES) search methods and their application in drug discovery, specifically for promoting healthy aging. GES searching is a powerful technology facilitating the identification of drugs for treating diseases and drug repurposing. This is achieved by identifying drugs in GES databases inducing signatures similar to query GESs obtained from diseased samples or drug treatments. The new connections are useful for developing pharmacological interventions. This dissertation is divided into the following three components. First, I developed the signatureSearch R/Bioconductor package that integrates existing and novel methods for GES searching and functional enrichment analysis (FEA). Subsequently, I tested the performance of different GES search methods. They represent the first systematic performance tests of these methods in the field. Second, I applied signatureSearch to the human healthy aging field to reveal insights into longevity associated (LA) drugs and their targets by searching the Integrated Network-based Cellular Signatures (LINCS) database. For this, I assessed the performance of LINCS drugs, inducing GESs representative for their mechanism of action (MOA), by computing for each MOA a recall score based on the GES similarity of the corresponding drugs. The obtained recall scores were used to prioritize LA drugs in the downstream discovery. LA MOA categories along with the corresponding drugs were identified by querying LINCS with GESs of drugs present in LINCS and DrugAge, and scoring the enrichment of each MOA. The corresponding LA pathways were identified via global mapping of targets of LA drugs and MOA categories. Next, I searched LINCS with the GESs from 11 well-studied LA drugs and one longevity phenotype. To identify LA pathways, the targets of the newly identified LA drugs were used for FEA. The results from the three steps were integrated and then interrogated with a combinatorial approach to select the most reliable set of LA drugs and targets. Collectively, this study identified a list of drugs, targets and pathways useful for pharmacological lifespan extension strategies. Third, I developed several data packages to incorporate in signatureSearch detailed annotations of drugs and targets from different community databases.