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Systems and chemical biology approaches to study cell function and response to toxins

Jiang, Yingying

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Abstract

Toxicity is one of the main causes of failure during drug discovery, and of withdrawal once drugs reached the market. Prediction of potential toxicities in the early stage of drug development has thus become of great interest to reduce such costly failures. Since toxicity results from chemical perturbation of biological systems, we combined biological and chemical strategies to help understand and ultimately predict drug toxicities. First, we proposed a systematic strategy to predict and understand the mechanistic interpretation of drug toxicities based on chemical fragments. Fragments frequently found in chemicals with certain toxicities were defined as structural alerts for use in prediction. Some of the predictions were supported with mechanistic interpretation by integrating fragmentchemical, chemical-protein, protein-protein interactions and gene expression data. Next, we systematically deciphered the mechanisms of drug actions and toxicities by analyzing the associations of drugs’ chemical features, biological features and their gene expression profiles from the TG-GATEs database. We found that in vivo (rat liver) and in vitro (rat hepatocyte) gene expression patterns were poorly overlapped and gene expression responses in different species (rat and human) and different tissues (liver and kidney) varied widely. Eventually, for further understanding of individual differences in drug responses, we reviewed how genetic polymorphisms influence the individual's susceptibility to drug toxicity by deriving chemical-protein interactions and SNP variations from Mechismo database. Such a study is also essential for personalized medicine. Overall, this study showed that, integrating chemical and biological in addition to genetic data can help assess and predict drug toxicity at system and population levels.

Item Type: Dissertation
Supervisor: Russell, Prof. Dr. Rob
Place of Publication: Heidelberg
Date of thesis defense: 1 February 2018
Date Deposited: 16 Mar 2018 11:26
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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