Molkentin Jeffery D, Robbins Jeffrey
Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH, USA.
J Mol Cell Cardiol. 2009 Feb;46(2):130-6. doi: 10.1016/j.yjmcc.2008.09.002. Epub 2008 Sep 19.
Over the past 20 years generation and subsequent characterization of genetically modified mouse models has revolutionized our understanding of disease-gene relationships and suggested numerous therapeutic targets for human disease. Cardiac biology has perhaps benefited more than most fields from the advent of modern genetic approaches in the mouse by providing a 3-dimensional integrated platform for phenotypic dissection of single gene function, largely replacing the unitary relationships derived from 2-dimensional cell culture-based platforms. Indeed, cardiac hypertrophy and end-stage heart failure are whole organ phenomena that occur within a dynamic neuroendocrine milieu, a backdrop that cannot be adequately modeled in cultured myocytes. Here we advocate the use of genetically modified mouse models for studying cardiac biology and show how, if employed properly, these models will continue to provide highly reliable data sets that suggest disease-gene relationships and novel therapeutic targets. In addition to a discussion of proper technique and controls, we will highlight examples of genetic approaches in the mouse that suggest novel disease relationships and therapeutic treatments for human heart failure, insights not possible with other experimental systems. In the preceding review/editorial by Cook, Clerk and Sugden, a number of strong arguments are made detailing the potential short comings associated with genetic approaches in the mouse as a means of unraveling cardiac disease mechanisms. We take very little issue with these arguments per se, although here we attempt to put these shortcomings into a greater context that extends beyond a single experimental setting, as well as to carefully construct a counterpoint that delineates the advantages of genetic approaches in the mouse compared with any other system currently in use in cardiovascular biology.
在过去20年里，转基因小鼠模型的构建及其后续特性分析彻底改变了我们对疾病-基因关系的理解，并为人类疾病提出了众多治疗靶点。心脏生物学领域或许比大多数领域从现代小鼠遗传学方法的出现中获益更多，因为它提供了一个三维综合平台，用于对单基因功能进行表型剖析，在很大程度上取代了基于二维细胞培养平台得出的单一关系。事实上，心脏肥大和终末期心力衰竭是发生在动态神经内分泌环境中的全器官现象，而这种背景在培养的心肌细胞中无法得到充分模拟。在此，我们提倡使用转基因小鼠模型来研究心脏生物学，并展示如果正确使用，这些模型将如何继续提供高度可靠的数据集，从而揭示疾病-基因关系和新的治疗靶点。除了讨论适当的技术和对照外，我们还将重点介绍小鼠遗传学方法的实例，这些实例揭示了与人类心力衰竭相关的新疾病关系和治疗方法，而这些见解是其他实验系统无法提供的。在Cook、Clerk和Sugden之前的综述/社论中，提出了许多有力论据，详细阐述了将小鼠遗传学方法作为揭示心脏疾病机制手段可能存在的潜在缺陷。我们本身对这些论据并无太多异议，不过在此我们试图将这些缺陷置于更广泛的背景中，这个背景不仅仅局限于单一实验环境，同时还精心构建一个对立面，以阐明小鼠遗传学方法相较于目前心血管生物学中使用的任何其他系统所具有的优势。
