Vascular development requires a complex series of events during which endothelial cells differentiate from angioblast progenitors and assemble into the dorsal aorta and the cardinal vein, comprising the original circulatory loop. Arteries and veins are morphologically, functionally and molecularly different. How this distinction is established at cellular and molecular levels in the early stage of vasculogenesis is largely unknown. New genetic evidence from zebra fish studies suggests that the Notch signal transduction pathway is required for vascular specification. The gridlock gene, encoding an Enhancer of Split-related bHLH protein, mediates Notch signaling to promote development of the embryonic arteries. The research proposal explains how cellular and genetic analysis are used in zebra fish to understand the role of notch-gridlock pathway in regulating arterial/venous endothelial fate of angioblasts. Specially, this proposal first aims to identify potential cell-cell interactions by following angioblast migration. Next, experiments are designed to examine expression pattern of Notch signaling components in vascular development, as well as to determine the fate of individual angioblasts that are incapable of normal Notch signaling. The final experiments are proposed to test the mechanism by which gridlock mediates Notch signaling via a negative feedback loop. As fundamentals of vascular development are conserved between vertebrates and mammals, understanding the notch-gridlock signaling pathway in zebrafish will provide insights into mechanisms of vascular development as well as advance our understanding of etiologies of many human arterial diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL073348-01A1
Application #
6720621
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Srinivas, Pothur R
Project Start
2003-12-23
Project End
2008-11-30
Budget Start
2003-12-23
Budget End
2004-11-30
Support Year
1
Fiscal Year
2004
Total Cost
$302,000
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Jin, Daqing; Ni, Terri T; Sun, Jianjian et al. (2014) Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport. Nat Cell Biol 16:841-51
Williams, Charles; Kim, Seok-Hyung; Ni, Terri T et al. (2010) Hedgehog signaling induces arterial endothelial cell formation by repressing venous cell fate. Dev Biol 341:196-204
Zeng, Xin-Xin I; Zheng, Xiangjian; Xiang, Yun et al. (2009) Phospholipase D1 is required for angiogenesis of intersegmental blood vessels in zebrafish. Dev Biol 328:363-76
Jin, Daqing; Ni, Terri T; Hou, Jia et al. (2009) Promoter analysis of ventricular myosin heavy chain (vmhc) in zebrafish embryos. Dev Dyn 238:1760-7
Qu, Xianghu; Jia, Haibo; Garrity, Deborah M et al. (2008) Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish. Dev Biol 317:486-96
Ni, Terri T; Lemon, William J; Shyr, Yu et al. (2008) Use of normalization methods for analysis of microarrays containing a high degree of gene effects. BMC Bioinformatics 9:505
Chopra, Sameer S; Watanabe, Hiroshi; Zhong, Tao P et al. (2007) Molecular cloning and analysis of zebrafish voltage-gated sodium channel beta subunit genes: implications for the evolution of electrical signaling in vertebrates. BMC Evol Biol 7:113
Jia, Haibo; King, Isabelle N; Chopra, Sameer S et al. (2007) Vertebrate heart growth is regulated by functional antagonism between Gridlock and Gata5. Proc Natl Acad Sci U S A 104:14008-13
Wang, Yue-Xiang; Qian, Lin-Xi; Liu, Dong et al. (2007) Bone morphogenetic protein-2 acts upstream of myocyte-specific enhancer factor 2a to control embryonic cardiac contractility. Cardiovasc Res 74:290-303
Rutenberg, Joshua B; Fischer, Andreas; Jia, Haibo et al. (2006) Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Development 133:4381-90

Showing the most recent 10 out of 11 publications