Van Eyk, Dunn - Proteomic and Genomic Analysis of Cardiovascular Disease - 2003 (522919), страница 26
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An example is the recent publication of the effect of beta blockers in the setting to understand heart failure. It appears that only in patients when the beta blockade can alter the cardiac contractile protein such as the myosin isoforms that the patientwill benefit with respect to reverse remodeling and improvement in clinical outcome. Therefore the availability of microarrays will now offer an unprecedentedopportunity to define the diverse targets that are affected by a certain therapeuticintervention, and define the true biological impact of a certain treatment strategy.This will be particularly important in the setting of heart failure, involving a largecomplex of pathophysiological pathways.4.16AcknowledgementsThe work is supported in part by grants from the Heart and Stroke Foundation ofOntario, and the Canadian Institutes of Health Research (CIHR).4.17 References4.17References123456789Ho KK, Pinsky JL, Kannel WB, Levy D.The epidemiology of heart failure: TheFramingham Study.
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This adaptation of the nuclear activity is the direct consequenceof variations in physiological conditions, and is strongly associated with the adaptation of both metabolic [10–14] and contractile [15] properties of the heart. Alarge-scale analysis of the regulation of gene expression in response to changes inphysiological parameters is the goal of functional genomics.Because of its fundamental function for the organism, the heart is extraordinarily receptive to variations of extracellular conditions, which are often referred toas a “stress” for the cardiac myocyte: increased contractile performance [16], oxygen deprivation [17, 18], burst of free radicals [19], endothelial dysfunction [20], increased preload [21, 22], cellular stretch [23] are just a few examples of thechanges in extracellular conditions that directly affect the cardiac cell.
All thesestimuli, either physiological or deleterious, are detected by different sensors (receptors, ion channels or transmembrane proteins) [24], relaying the informationto transmitters (signaling pathways) [23], which in turn regulate the activity of theeffectors (enzymes and transcription factors) [25, 26]. The effectors are directly responsible for the adaptation of the expression of different genes in response tothe initial stimulus (Fig. 5.1).
In other words, the gene expression profile is the“end-point” of the effects of any stimulus on the heart (Fig. 5.1). Determining thisprofile helps deciphering the fundamental characteristics of a specific stimulus.Comparing the profiles in response to different stimuli also helps to determinethe similarities and differences between these stimuli. The accumulation of geneprofiles in response to different conditions leads to the elaboration of a compendium of cardiac gene expression.
This compendium can subsequently be used, forinstance, to analyze the effects of a drug on cardiac gene expression in differentphysiological conditions [27].Genomics and proteomics are complementary, but they also address very different questions. The analysis of gene expression as an “end-point” of the effects of aspecific stimulus on the heart is in sharp contrast with the concept of the gene asa “starting point” leading to the expression of specific proteins (Fig. 5.1). The“end-point strategy” consists in looking at the gene not as a protein provider, butProteomic and Genomic Analysis of Cardiovascular Disease.Edited by Jennifer E. van Eyk, Michael J. DunnCopyright © 2003 WILEY-VCH Verlag GmbH & Co.
KGaA, WeinheimISBN: 3-527-30596-3825 Genomics by Subtractive HybridizationGenome profile as an “end-point” ora “starting point”. In the “end-point”approach, the genomic profile is the result ofthe transmission of extracellular stimuli to theFig. 5.1nucleus. In the “starting point” approach, thegene leads to the production of proteins,which needs to be further studied by proteomics.as an integrator of incoming information. Considering that a cell is viable as longas it has a functional nucleus, gene expression profiling is a way to evaluate thenuclear activity of a specific cell type in a specific milieu. We know that, in turn,the increased expression of a gene does not automatically result in the increasedexpression of the corresponding protein, and that the expression of a specific protein can be regulated by non-transcriptional mechanisms.
We also know that atranscript is not necessarily targeted to the translational machinery, as shown recently with the concept of gene silencing by RNA interference [28, 29].The “end-point” strategy is a way to better understand the mechanisms of cardiac adaptation. For example, we often refer to the concept of “stress response” tocharacterize the response of the heart to conditions as diverse as transient ischemia, aortic banding or catecholamines infusion. Although these conditions canall induce the increased expression of “stress” gene markers (such as the atrial natriuretic factor or proto-oncogenes), each of them can activate the expression ofspecific subsets of genes, such as specific heat-shock proteins, anti-apoptotic proteins, metabolic enzymes, activators of protein translation or others.
Therefore,the response of the myocardium to “stress” depends on the context and the stimulus.5.1 Strategies and Limitations of Genome Profiling5.1Strategies and Limitations of Genome ProfilingSeveral parameters must be taken into consideration to perform functional genomics and gene profiling. These include, but are not restricted to, a biological problem, a good model and a reliable technique.5.1.1The Biological ProblemThe biological problem, or the question asked, is usually obscured by the fact thatfunctional genomics is perceived as a “fishing expedition”. Although it is true thatgenomics studies are not always hypothesis-driven, very expensive and time-consuming experiments can rapidly turn into deep frustration if they are conductedin the absence of an underlying biological question.
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