The long-term goal of this proposal is to understand the genetic mechanisms that lead to the formation and functional differentiation of the heart in the model system of the fruit fly Drosophila. This is the first genetic model system in which a defined set of genes has been identified that specify and correctly position the heart within the embryo. In pursuit of this goal, we have established that global embryonic positioning cues, encoded by the secreted factors wingless (Wnt) and dpp (TGF-beta), act in conjunction with the transcription factors Tinman (homeodomain protein) and Pannier (GATA factor), which provide essential mesodermal context information, to allow initiation of heart specification. Remarkably, molecular mechanisms and gene identities responsible to make a fly heart are conserved within the animal kingdom, and have paved the way for understanding fundamental aspects of congenital heart disease. Congenital heart defects are the most common developmental anomaly and are the leading non-infectious cause of mortality in newborns. The Drosophila heart has become an excellent model for unraveling the basic mechanisms of cardiogenesis, and for finding crucial components involved in cardiac differentiation. Here, we propose to continue to exploit the genetic tools and reagents available in Drosophila to elucidate the basis of heart formation (aim 1) and function (aim 2).
In aim 1, we propose to examine the genetic and biochemical interactions among the mesodermal transcription factors Tinman, Pannier and a new set of players, the T-box factors Neuromancer 1 (H15) and 2 (H15r), in specifying heart.
In aim 2, we plan to examine the role of these transcriptional regulators and select targets in establishing normal heart function. To begin to understand the genetic controls of cardiac physiology, we will also identify and study new gene functions that affect this process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054732-11
Application #
7014559
Study Section
Special Emphasis Panel (ZRG1-CDD (01))
Program Officer
Schramm, Charlene A
Project Start
1995-08-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
11
Fiscal Year
2006
Total Cost
$466,279
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Zanon, Alessandra; Kalvakuri, Sreehari; Rakovic, Aleksandar et al. (2017) SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila. Hum Mol Genet 26:2412-2425
Sessions, Ayla O; Kaushik, Gaurav; Parker, Sarah et al. (2017) Extracellular matrix downregulation in the Drosophila heart preserves contractile function and improves lifespan. Matrix Biol 62:15-27
Diop, Soda Balla; Birse, Ryan T; Bodmer, Rolf (2017) High Fat Diet Feeding and High Throughput Triacylglyceride Assay in Drosophila Melanogaster. J Vis Exp :
Zarndt, Rachel; Walls, Stanley M; Ocorr, Karen et al. (2017) Reduced Cardiac Calcineurin Expression Mimics Long-Term Hypoxia-Induced Heart Defects in Drosophila. Circ Cardiovasc Genet 10:
Blice-Baum, Anna C; Zambon, Alexander C; Kaushik, Gaurav et al. (2017) Modest overexpression of FOXO maintains cardiac proteostasis and ameliorates age-associated functional decline. Aging Cell 16:93-103
Gan, Zhuohui; Powell, Frank L; Zambon, Alexander C et al. (2017) Transcriptomic analysis identifies a role of PI3K-Akt signalling in the responses of skeletal muscle to acute hypoxia in vivo. J Physiol 595:5797-5813
Hartley, Paul S; Motamedchaboki, Khatereh; Bodmer, Rolf et al. (2016) SPARC-Dependent Cardiomyopathy in Drosophila. Circ Cardiovasc Genet 9:119-29
Achal, Madhulika; Trujillo, Adriana S; Melkani, Girish C et al. (2016) A Restrictive Cardiomyopathy Mutation in an Invariant Proline at the Myosin Head/Rod Junction Enhances Head Flexibility and Function, Yielding Muscle Defects in Drosophila. J Mol Biol 428:2446-2461

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