Brain defects induced by embryonic exposure to modulators of calcium signaling

胚胎暴露于钙信号调节剂诱发的脑缺陷

基本信息

批准号：
8605886
负责人：
ROBBERT J CRETON
金额：
$ 24.35万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605886
关键词：
Affect Angina Pectoris Animal Model Arrhythmia Behavior Behavioral Bilateral Biological Models Brain Ca(2+)-Transporting ATPase Calcium Calcium Signaling Candidate Disease Gene Cations Cells Cellular biology Defect Development Developmental Biology Developmental Process Dorsal Dose Embryo Embryonic Development Endoplasmic Reticulum Environment Ethology Experimental Genetics Exposure to Eye Gene Expression Profile Genes Goals Handedness Holoprosencephaly Human Hypertension Image Laboratories Lateral Left Life Medicine Mesoderm Migraine Mutation Neurosciences Pattern Pharmacologic Substance Phenotype Play Pregnancy Prosencephalon Proteins Randomized Risk Risk Assessment Role Spasm Staging Syndrome Testing Time Work Zebrafish base drinking water gastrulation inhibitor/antagonist neural patterning overexpression public health relevance response

项目摘要

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.

描述（由申请人提供）：调节钙信号传导的药物已成功用于治疗高血压，心律不齐，心绞痛和偏头痛。但是，由于动物模型系统中的研究表明，胚胎发育过程中的微妙钙操纵可以诱导特定的大脑缺陷，因此它们在医学中的广泛使用和随后的环境排放涉及。由于可能直接或间接影响钙信号传导的大量药物，缺乏有关敏感发育时期的基本信息以及对脑发育和行为的潜在多效影响，因此很难评估人脑发育的潜在风险。我们的长期目标是更好地了解钙信号的调节如何影响大脑发育和行为。将使用斑马鱼作为模型系统实现这一长期目标。斑马鱼胚胎在遗传和实验性操作中可以迅速和外部发展，并开发可预测的神经模式和行为，这些神经模式和行为已详细描述。指导该项目的具体假设是，钙信号传导的调节因子通过在有限的灵敏度窗口中改变特定的发育过程来诱导大脑中的横向缺陷。该假设将以三个特定的目的进行检验，以整合细胞生物学，发育生物学，神经科学和伦理学的方法，以概述钙信号调节器影响大脑发育的机制。 1）第一个目的是识别钙信号的调节剂，该调节剂会诱导大脑横向缺陷。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作用。 2）第二个目的是确定预测大脑特定侧向缺陷的发展的钙模式。钙模式将以未经处理的胚胎和暴露于钙信号调节剂的胚胎中成像，这些钙信号传导导致脑发育和行为中的缺陷。 3）第三个目的是确定对钙敏感的基因表达模式，这些模式在大脑发育中起作用。我们将根据其在大脑的双侧分裂中的作用，它们在大脑中左右不对称的发展以及对钙调节的敏感性中所选择的三组候选基因。获得的结果将更好地理解对钙敏感的机制，这些机制在大脑的侧向发展中发挥作用，这对于风险评估和预防策略的发展非常重要。