Brain defects induced by embryonic exposure to modulators of calcium signaling

描述（由申请人提供）：调节钙信号的药物已成功用于治疗高血压、心律失常、心绞痛和偏头痛。然而，它们在医学上的广泛使用和随后在环境中的排放令人担忧，因为动物模型系统的研究表明，胚胎发育期间微妙的钙操纵可以诱发特定的脑缺陷。由于大量药物可直接或间接影响钙信号，缺乏关于敏感发育时间的基本信息，以及对大脑发育和行为的潜在多效性影响，因此难以评估其对人类大脑发育的潜在风险。我们的长期目标是更好地理解钙信号的调节如何影响大脑发育和行为。这一长期目标将以斑马鱼为模型系统来实现。斑马鱼胚胎发育迅速，外部发育，易于遗传和实验操作，并形成可预测的神经模式和行为，这些已经详细描述。指导本项目的具体假设是，钙信号的调节剂通过在有限的敏感性窗口内改变特定的发育过程来诱导脑侧性缺陷。这一假设将在细胞生物学、发育生物学、神经科学和行为学的三个具体目标中进行验证，以提供钙信号调节剂影响大脑发育的机制概述。1)第一个目标是确定钙信号的调节剂，诱导脑侧性缺陷。我们将确定神经模式和行为缺陷的剂量-反应曲线，并将检查潜在的协同效应。2)第二个目标是确定钙模式，以预测大脑中特定偏侧缺陷的发展。将对未经处理的胚胎和暴露于钙信号调节剂的胚胎进行钙模式成像，这些调节剂会诱发大脑发育和行为缺陷。3)第三个目标是确定在大脑发育中起作用的钙敏感基因表达模式。我们将研究三组候选基因，这些基因是根据它们在大脑双侧分裂中的作用、它们在大脑左右不对称发育中的作用以及它们对钙调节的敏感性来选择的。所获得的结果将更好地了解在脑侧性发展中起作用的钙敏感机制，这对风险评估和预防策略的制定具有重要意义。

DESCRIPTION (provided by applicant): 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.