Using Zebrafish for High-Throughput Screening of Novel Cardiovascular Drugs.
Using Zebrafish for High-Throughput Screening of Novel Cardiovascular Drugs.
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DOI：
10.1016/j.jacbts.2017.01.004
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
MacRae CA
中科院分区：
文献类型：
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作者：
Kithcart A;MacRae CA
心血管疾病仍然是现代药物发现的主要挑战。这些疾病是慢性的、复杂的，是遗传和环境之间复杂相互作用的结果，涉及多种细胞类型和许多全身性因素。临床事件通常是突然的，并且疾病可以是无症状的，直到高度病态的事件。靶点选择通常基于有限的信息，尽管在筛选中通常鉴定出高度特异性的药物，但其最终疗效通常会受到意外的全身反应、狭窄的治疗指数或大量毒性的影响。在过去的20年里，我们对心血管疾病复杂性的理解有了显著的增长，并且潜在的疾病机制的范围现在包括以前认为仅与心脏或血管疾病无关的途径，尽管有这些见解，大多数活性心血管药物来自非常少的药物类别，并且靶向非常有限的途径。这些药物通常最初用于特定适应症，然后偶然发现对其他心脏疾病有效，或以与其原始作用机制无关的方式有效。在这篇评论中，在体内筛选的基本原理进行了描述，并讨论了这种方法和功能基因组学的互补工作的斑马鱼的效用。目前在这种情况下的模型的局限性和需要仔细验证新的疾病领域也进行了说明。概述了大多数临床心血管疾病的复杂机制，并深入了解作为药物靶点的单一下游途径的局限性。斑马鱼被引入作为模式生物，特别是心血管生物学。潜在的方法来克服药物发现的障碍，面对复杂的生物学进行了讨论，包括在体内筛选斑马鱼遗传疾病模型。
Cardiovascular diseases remain a major challenge for modern drug discovery. The diseases are chronic, complex, and the result of sophisticated interactions between genetics and environment involving multiple cell types and a host of systemic factors. The clinical events are often abrupt, and the diseases may be asymptomatic until a highly morbid event. Target selection is often based on limited information, and though highly specific agents are often identified in screening, their final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index, or substantial toxicities. Our understanding of complexity of cardiovascular disease has grown dramatically over the past 2 decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in cardiac or vascular disease. Despite these insights, the majority of active cardiovascular agents derive from a remarkably small number of classes of agents and target a very limited number of pathways. These agents have often been used initially for particular indications and then discovered serendipitously to have efficacy in other cardiac disorders or in a manner unrelated to their original mechanism of action. In this review, the rationale for in vivo screening is described, and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. An overview is provided of the complex mechanisms underlying most clinical cardiovascular diseases, and insight is offered into the limits of single downstream pathways as drug targets. The zebrafish is introduced as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology are discussed, including in vivo screening of zebrafish genetic disease models.