RIP-CHIP in Drug Development
Microarrays are extensively used to evaluate the effects of compounds on gene expression in the cells. Most of the studies so far have analyzed the transcriptome of the cell. The basic assumption of this approach is that the changes in gene expression occ
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Introduction The process of drug development is a lengthy and laborious process in which a novel chemical entity, which has been identified to produce a beneficial effect in the human body, is subjected to rigorous testing to ensure safety and efficacy before it can be approved as a drug. In the very first phase of drug development (called preclinical testing), the investigational drug is extensively tested in the laboratory. These tests are done both in vitro (using cultured cells) and in vivo (by administering the drug on small animals, e.g., rodents). Since changes in gene expression at the molecular level can be detected before any biological symptoms appear, in vitro studies designed to study the changes in molecular genetic events that occur in a cell in response to the drug can greatly enhance drug development. It also leads to a better Sridar V. Chittur (ed.), Microarray Methods for Drug Discovery, Methods in Molecular Biology, vol. 632, DOI 10.1007/978-1-60761-663-4_10, © Humana Press, a part of Springer Science+Business Media, LLC 2010
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understanding of the mode of action of the drug and any potential side effects it may generate. Most often, these genetic events are studied in terms of global changes in gene expression levels. High-throughput technologies such as microarrays can be used to quantitatively study the steady-state mRNA level of cells (also known as the transcriptome) and can greatly reduce the time and cost involved in the evaluation of a new drug (1–3). In fact, the US-FDA has set up a database for storing microarray gene-expression data specifically for pharmaco- or toxicogenomic studies (4). However, the accumulated level of RNA does not always directly correlate with the level of protein output of the cell. All events, beginning with the transcription of mRNA to processing, transport, localization, stability, degradation, and translation are regulated by various RNA-Binding Proteins (RBPs), and contribute significantly to the final amount of protein product produced (for a review see ref. (5–7)). In addition, RBPs can sequester functionally-related mRNAs together to allow coordinated expression of functionally related genes. These “posttranscriptional operons” may allow the cell to generate a rapid response to an incoming signal by regulating the stability and translation of specific mRNAs (8). The posttranscriptional operon model is able to explain the discordance that is often observed between the levels of mRNA and the protein of any given gene. Just because a gene is transcribed does not necessarily mean that it is translated; it may be kept on hold, or degraded by various RBPs. Experimental evidence from many different labs in recent years has demonstrated that mRNAs which either participate in a common function or subcellular localization tend to be part of the same RNP complex, thus providing further evidence for the existence of posttranscriptional operons. Often, these RBPs bind to mRNAs through elements that contain sequence and structural specificity a
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