Drug discovery through functional screening in the Drosophila heart.
Although advancements in the preventive and therapeutic strategies of cardiac diseases have successfully improved the prognosis of many types of cardiac diseases, they are still challengeable targets because of their high mortality and large medical expenses. Moreover, because heart function is tightly associated with quality of life, it is important to elucidate the genetic and molecular basis of disease progression. One of the recent advances for assessing protein function is reverse chemical genetics, which has the advantages that complement classical reverse genetics and should advance efforts at drug discovery for many diseases. Toward that end an appropriate biological assay system is required to describe specific heart phenotypes. Recent studies have shown that many aspects of Drosophila heart development and function are similar to those observed in the human heart, making Drosophila a useful model system with the advantage of a simpler genetic organization and shorter life span. Here we describe several assay systems that can be used to characterize Drosophila heart function. The first method is an external electrical pacing assay that is used to assess the response to stress in the adult fly. The incidence of pacing-induced heart dysfunction measured by this method strongly correlates with natural aging and mutation in genes known to be involved in human cardiac dysfunction. Consequently, this method can be used to identify unapparent heart failure phenotypes. This procedure is applicable for both genetic and pharmacological screening. The second method is an image-based heart performance assay. This method provides details of the dynamics of heart contraction in real time similar to clinical echocardiography. This method may be used for secondary drug screening as well as for more detailed analysis of the genetic and pharmacological phenotypes of Drosophila hearts.
Akasaka
Takeshi
T
Burnham Institute for Medical Research, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, La Jolla, CA, USA.
Ocorr
Karen
K
D000375:Aging / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004558:Electric Stimulation; D005260:Female; D017344:Genes, Insect; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006333:Heart Failure / Q000209:etiology; D006801:Humans; D008297:Male; D010641:Phenotype