Léger J, Swynghedauw B
INSERM-U533, Ouest Génopole, faculté de médecine, 1, rue Gaston Veil, BP 53508, 44035 Nantes 1.
Arch Mal Coeur Vaiss. 2006 Mar;99(3):231-6.
Cell biology is in transition from reductionism, to a more integrated science which is now preoccupied by molecular interactions acting in modules. Large-scale quantitative analysis of gene expression, including cDNA microarrays and proteomic analysis, is now applied to heart failure and atherosclerosis. The technology is still at the beginning and is limited by variations in the array platforms and gene products as well as sensitivity or specificity of the selected probes. These limitations are progressively going to be reduced, but still they do exist. Biological systems are scale free networks made from genes, proteins or traits that interact one another and form networks and functional modules. Networks emerge through the addition of new nodes which are preferentially attached to more connected nodes to form hubs, according to the "rich-gets-richer" mechanism, and there are large networks which include central genes (nexus). Both hubs and nexus are attractive candidate for targeting new therapy. An important study from King JY et al. (Physiol Genomics 2005; 23: 103-18) exemplifies this concept by showing the first realistic pathways to understand atherosclerosis. The 4 steps of the design are based on histological grading and microarrays analysis and include an association network constructed from PubMed and the construction of sub-networks in which genes whose expression was differentially regulated were indicated. Connectivity analysis networks revealed new important modular pathways. In heart failure, no attempts have been made to organize the data into functional modulus. Since the causes of heart failure are well documented, the problem is to identify functional modules responsible for myocardial dysfunction. Several potential functional modules can be identified so far. Indeed, cardiac remodeling results from two types of changes in gene expression, namelly the reexpression of the foetal programme which has a mechanical origin and several well documented interfering determinants that modified the basic remodelling, including senescence, obesity, diabetes, ischemia, and the neurohormonal reaction.
细胞生物学正从还原论转向一门更加综合的科学，如今这门科学专注于模块中发生的分子相互作用。基因表达的大规模定量分析，包括cDNA微阵列和蛋白质组分析，目前已应用于心力衰竭和动脉粥样硬化研究。这项技术仍处于起步阶段，受到阵列平台和基因产物的差异以及所选探针的灵敏度或特异性的限制。这些限制将逐步减少，但仍然存在。生物系统是由相互作用并形成网络和功能模块的基因、蛋白质或性状构成的无标度网络。根据“富者更富”机制，网络通过添加新节点而出现，这些新节点优先连接到连接更多的节点以形成枢纽，并且存在包含核心基因（连接点）的大型网络。枢纽和连接点都是新治疗靶点的有吸引力的候选者。金JY等人（《生理基因组学》2005年；23: 103 - 18）的一项重要研究通过展示理解动脉粥样硬化的首个实际途径例证了这一概念。该设计的4个步骤基于组织学分级和微阵列分析，包括从PubMed构建的关联网络以及构建其中显示基因表达差异调节的子网络。连通性分析网络揭示了新的重要模块化途径。在心力衰竭方面，尚未有人尝试将数据组织成功能模块。由于心力衰竭的病因已有充分记录，问题在于识别导致心肌功能障碍的功能模块。到目前为止，可以识别出几个潜在的功能模块。实际上，心脏重塑源于基因表达的两种变化，即具有机械起源的胎儿程序的重新表达以及几个有充分记录的干扰决定因素，这些因素改变了基本的重塑过程，包括衰老、肥胖、糖尿病、缺血和神经激素反应。
