This proposal addresses the utility of Drosophila as a model for the genetic dissection of the polygenic basis for the etiology of organ failure. Specifically, we will test the hypothesis that segregating variants in genes that regulate the physiology, endocrinology, and morphogenesis of the heart contribute to age-dependent loss of heart function in adult flies. In the process, we expect to identify novel genes that affect the onset of heart disease. There are two distinct classes of models for the genetic determination of complex diseases, namely the "common disease-common variant" and "preponderance of rare alleles of major effect" models. The former has been the dominant paradigm, but failure of many linkage studies and inconsistent replication of association with complex diseases is challenging its suitability. On the other hand, there is a clear need for new methodological approaches to the detection of rare alleles that contribute to polygenic disease. We propose here that dysfunction of the Drosophila heart, manifested as pacing-induced heart failure and arrhythmia is an ideal model. Careful visualization of heart function in inbred wild-type lines indicates that there are extreme genotypes that exhibit a range of abnormalities. After detailed assessment of the incidence of elevated or reduced heart failure and of arrhythmias in young and old flies we will carry out quantitative genetic analyses designed to (i) assess the capacity of the genetic background to modify the penetrance and expressivity of disease-promoting allelic combinations;(ii) document the capacity of naturally occurring alleles that affect different aspects of heart performance to complement and/or interact with one another;and (iii) map and clone ten or so rare major-effect heart disease susceptibility alleles. Transcriptional and metabolic profiling will also be performed to develop cardiac biomarkers. Project Narrative: This proposal uses a model organism to study how heart performance in old age may be affected by rare mutations. It combines classical genetic analysis with population genetics to find new genes involved in various aspects of cardiac dysfunction, and asks whether there are common features of susceptibility that might be detected with genomic tools.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085481-05
Application #
8225174
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Wang, Lan-Hsiang
Project Start
2008-03-20
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$514,677
Indirect Cost
$157,658
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Nishimura, Mayuko; Kumsta, Caroline; Kaushik, Gaurav et al. (2014) A dual role for integrin-linked kinase and ?1-integrin in modulating cardiac aging. Aging Cell 13:431-40
Reed, Laura K; Lee, Kevin; Zhang, Zhi et al. (2014) Systems genomics of metabolic phenotypes in wild-type Drosophila melanogaster. Genetics 197:781-93
Zhang, Zhi; Hsieh, Benjamin; Poe, Amy et al. (2013) Complex genetic architecture of cardiac disease in a wild type inbred strain of Drosophila melanogaster. PLoS One 8:e62909
Na, Jianbo; Musselman, Laura Palanker; Pendse, Jay et al. (2013) A Drosophila model of high sugar diet-induced cardiomyopathy. PLoS Genet 9:e1003175
Zhao, Jing; Arafat, Dalia; Brigham, Kenneth L et al. (2013) Genetic risk prediction in a small cohort of healthy adults in Atlanta. Genet Res (Camb) 95:30-7
Nishimura, Mayuko; Ocorr, Karen; Bodmer, Rolf et al. (2011) Drosophila as a model to study cardiac aging. Exp Gerontol 46:326-30
Buechling, Tina; Akasaka, Takeshi; Vogler, Georg et al. (2009) Non-autonomous modulation of heart rhythm, contractility and morphology in adult fruit flies. Dev Biol 328:483-92
Wessells, Robert; Fitzgerald, Erin; Piazza, Nicole et al. (2009) d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in Drosophila. Aging Cell 8:542-52
Taghli-Lamallem, Ouarda; Akasaka, Takeshi; Hogg, Grant et al. (2008) Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype. Aging Cell 7:237-49