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Title: Investigation of the Regulatory Roles of Micrornas by Systems Biology Approaches
Authors: YANG YANG
Keywords: Systems Biology, MicroRNAs, P53, Apoptosis
Issue Date: 20-Jan-2011
Source: YANG YANG (2011-01-20). Investigation of the Regulatory Roles of Micrornas by Systems Biology Approaches. ScholarBank@NUS Repository.
Abstract: Systems biology is a field of increasing importance in biology research. It aims to study the functioning of inter- and intra-cellular dynamic networks, using signal- and system-oriented approaches. In this thesis, we apply this idea to investigate the regulatory roles of microRNAs. MicroRNAs are small non-coding RNAs, which inhibit the gene expression by binding to the target genes. Mounting evidence shows that microRNAs are involved in many crucial biological processes, including cancer. Among them, one critical process---p53-dependent apoptosis pathway---is selected to accommodate microRNA to conduct the study. During the investigation, we solve the core problem step by step. First of all, the surrounding network about the well-known protein p53 is investigated. Ordinary differential equations are built to describe the underlying mechanisms. Based on the mathematical model, two novel phenomena are predicted to describe the stability change and frequency shift due to the varying levels of external stimulus. Experiment guidelines to validate these predictions are also provided accordingly. Secondly, we employ a discrete formalism---Petri net---to model a large-scale network, p53-dependent apoptosis pathway. One challenge in systems biology is how to obtain an accurate and predictable computational model for the biomolecular networks under study. Therefore, to enhance the reliability, we propose two approaches to check the model's correctness, which are based on invariant analysis and reachability analysis, respectively. The case studies show good competency of those approaches. Thirdly, we tackle the core problem about microRNA. The prediction of microRNAs' targets presents a big obstacle in microRNA studies. Because bioinformatics tools offer enormous targets, most of which are believed to be false positive. Model checking based method is developed to address this issue. MicroRNA and its targets are put into p53-dependent apoptosis pathways. Then, the validity of the predicted targets is determined by the comparisons between models with and without considering microRNA's inhibition on respective targets. The experimental evidence provides the evaluation criteria. In case of lacking evidence, experimental design schemes are provided based on the desired specifications as well. In summary, in this thesis, we illustrate the whole procedure to investigate the regulatory role of microRNAs by addressing the problem of microRNA target validation. In addition, the approach developed here may finally evolve into a formal method to comprehensively and rapidly validate target mRNAs for the microRNA, which may help us to understand cancer better and design new therapeutic strategies for cancer.
Appears in Collections:Ph.D Theses (Open)

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