Pharmaceuticals that modulate calcium signaling are successfully used for treating high blood pressure, heart arrhythmias, angina pectoris, and migraine. However, their widespread use in medicine and subsequent discharge in the environment is concerning, since studies in animal model systems have shown that subtle calcium manipulations during embryonic development can induce specific brain defects. The potential risk for human brain development is difficult to evaluate because of the large number of pharmaceuticals that can affect calcium signaling either directly or indirectly, a lack of basic information on the sensitive developmental times, and the potentially pleiotropic effects on brain development and behavior. Our long-term goal is to better understand how modulation of calcium signaling affects brain development and behavior. This long-term goal will be pursued using zebrafish as a model system. Zebrafish embryos develop rapidly and externally, are accessible to genetic and experimental manipulation, and develop predictable neural patterns and behaviors, which have been described in detail. The specific hypothesis that guides this project is that modulators of calcium signaling induce laterality defects in the brain by changing specific developmental processes during a limited window of sensitivity. This hypothesis will be tested in three specific aims that integrate approaches in cell biology, developmental biology, neuroscience, and ethology to provide an overview of the mechanisms by which modulators of calcium signaling affect development of the brain. 1) The first aim is to identify modulators of calcium signaling that induce laterality defects in the brain. We will determine the dose-response curves for defects in neural patterning and behavior and will examine potential synergistic effects. 2) The second aim is to identify calcium patterns that predict the development of specific laterality defects in the brain. Calcium patterns will be imaged in untreated embryos and in embryos exposed to modulators of calcium signaling that induce defects in brain development and behavior. 3) The third aim is to identify calcium-sensitive gene expression patterns that play a role in brain development. We will examine three sets of candidate genes that were selected based on their role in bilateral division of the brain, their role in development of left-right asymmetry in the brain, and their sensitivity to calcium modulation. The obtained results will provide a better understanding of calcium-sensitive mechanisms that play a role in the development of laterality in the brain, which is important for risk assessment and the development of preventative strategies.

Public Health Relevance

This project is focused on brain defects and behavioral defects caused by embryonic exposures to pharmaceuticals that modulate calcium signaling. The obtained results will provide a better understanding of the basic mechanisms by which modulators of calcium signaling affect brain development. These mechanisms are important, since human embryos may inadvertently be exposed to modulators of calcium signaling by maternal use of medicine during early pregnancy or by trace concentrations of pharmaceuticals in the environment and drinking water.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD060647-05
Application #
8605886
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Urv, Tiina K
Project Start
2010-03-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$243,451
Indirect Cost
$88,553
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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