Physiological Genomics of the Zebrafish Heart

人类基因组计划的成功完成突出了对实验方法的重大需求，这些方法旨在将基因组信息与整个生物体中的复杂生理现象联系起来。识别那些对生长和功能的正常发育至关重要的基因将是描述潜在调控基因组网络的重要的第一步。斑马鱼已被证明是研究心血管疾病遗传基础的一个很好的模型系统。基于表型的遗传筛查揭示了心脏发生中的一系列单一成分，有助于剖析发育逻辑。这项提议将这种方法扩展到扰乱早期心脏生长和/或功能的突变，在广泛的方式上探索生理基因组学工作的可行性。该项目有两个具体目标：1)定位克隆从大型遗传筛选中分离出的40种生理表型的突变基因。这些表型是那些心管最初形成，产生心腔，但随后无法正常生长或以适当的节奏有力收缩的表型。2)系统地表征表型，并开始对体内表型效应和器官和细胞水平的表型效应进行更准确的分类。所有突变都将立即提供给社区，并通过基因突变和逐步精炼的表型信息进行注释。这一独特的资源将为随后在斑马鱼、其他生物和最终人类中研究那些对心血管系统正常生长和功能至关重要的通路提供切入点。

The successful completion of the Human Genome Project has highlighted a major need for experimental approaches designed to relate genomic information to complex physiologic phenomena in the whole organism. The identification of those genes critical for the normal development of growth and function will be an important first step in the characterization of the underlying regulatory genomic networks. The zebrafish has proven an excellent model system for the study of the genetic basis of cardiovascular form. Phenotype based genetic screens have revealed a series of unitary components in cardiogenesis helping to dissect the logic of development. This proposal extends this approach to mutations that perturb early heart growth and/or function, in a broad way exploring the feasibility of a physiologic genomics effort. The project has two specific aims: 1) To clone positionally the mutated genes responsible for 40 physiologic phenotypes isolated from large genetic screens. These phenotypes are those in which the heart tube forms initially, generates chambers, but then fails to grow normally or to contract vigorously and with proper rhythmicity. 2) To systematically characterize the phenotypes and to begin to more precisely categorize the phenotypic effects in vivo and at the level of both organ and cell. All mutations will be made immediately available to the community, annotated by gene mutation and progressively refined phenotypic information. This unique resource will provide the entry points for subsequent investigation in zebrafish, other organisms and eventually humans, of those pathways central to the normal growth and function of the cardiovascular system.