MacRae Lab

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The zebrafish occupies a unique niche between tractable invertebrate organisms such as C. elegans and Drosophila, and higher vertebrates with closer homology to humans, such as rodents. We have established that even by 48 hours post fertilization there is remarkable physiologic and pharmacologic homology between the larval zebrafish and adult humans. At this stage of development the zebrafish can be maintained in 96 or 384 multi-well plates. We have developed a number of automated quantitative assays for zebrafish physiologic variables including heart rate, myocardial contractility, and blood flow. These assays are capable of being automated, allowing high-throughput quantitative studies of the role of genes, environment and their interactions in integrative vertebrate physiology.


There are numerous applications of these technologies including genetic screens for physiologic rather than morphologic endpoints, systematic pharmacogenetics and chemical suppressor screens. Currently, we are undertaking a dominant and recessive screen for modifiers of drug-induced cardiotoxicity. This screen will define the genes responsible for sensitivity and resistance to IKr-mediated repolarization toxicity (the most common cause of drug withdrawal from the market), which then will be studied as candidates for human susceptibility to the same drugs as well as illuminating the basis of normal repolarization. Similar cross talk between human and zebrafish studies might be imagined in systematic approaches to a host of other biological problems.

 

Zebrafish as a model of vertebrate development

Transparency of embryos allows explicit definition and characterization of developmental cardiovascular phenotypes