Cyclic Nucleotides and the Response to Sonic Hedgehog

环核苷酸和对 Sonic Hedgehog 的反应

• 批准号: 6629399
• 负责人: HENK ROELINK
• 金额: $ 15.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629399
• 关键词: biological signal transduction; chick embryo; congenital brain disorder; cyclic AMP; cyclic GMP; developmental neurobiology; embryo /fetus disorder; embryo /fetus toxicology; environmental exposure; forskolin; gene environment interaction; immunocytochemistry; neural plate /tube; neurotoxicology; neurotoxins; nucleotides; phosphodiesterases; protein kinase A; tissue /cell culture; veratrum alkaloid

Description: The Sonic Hedgehog is a signaling molecule that is required for normal development of the central nervous system. The response to Shh is complex, and can be changed by environmental compounds like cyclopamine. Changes in the Shh response result in a specific type of embryo malformations characterized by defects of the neural midline, like holoprosencephaly, which can be reflected in the face as cyclopia or hypotelorism. All cell types in the ventral neural tube develop as a consequence of Shh signaling, and it is likely that small changes in the Shh response has subtle effects on the formation of ventral cell types. This in turn might result in congenital neurological defects. It has been determined that the Shh response is influenced by the cyclic nucleotide concentration within the responding cells. Increasing the camp concentration attenuates the Shh response, while loss of the camp dependent kinase (PKA) activates the Shh response. These authors showed that increasing the cGMP concentration also enhances the response to Shh, suggesting a model in which the Shh response is dependent on the cyclic nucleotide concentration within the responsive cells, and that camp and cGMP have opposite effects on the Shh response. Several compounds present in the environment can alter the intracellular cyclic nucleotide concentration, either by activating GTP/ATP cyclases, enzymes that generate cyclic nucleotides, or by blocking phosphodiesterases, enzymes that degrade cyclic nucleotides. It is hypothesized that environmental compounds that change the cyclic nucleotide complement of a cell, alter Shh response in such cells, resulting in embryo malformations and thus birth defects. The hypothesis will be tested using sensitive assays of the Shh response in the chick embryo. It will be determined if environmental compounds that change the cyclic nucleotide complement of a cell interfere with normal Shh signaling in the developing neural tube in vivo, or in neural explants in vitro. In humans, exposure to the compounds that will be tested is either voluntary, like forskolin, or involuntary, like bacterial enterotoxins, but in either case little is known about their possible adverse effects on early embryos and thus as a cause of birth defects.

产品描述： 音速刺猬是一种信号分子， 中枢神经系统的发育。 对嘘的反应很复杂， 并且可以被环境化合物如环巴胺改变。 变化 Shh反应导致特定类型胚胎畸形 其特征是神经中线缺陷，如前脑无裂畸形， 可以反映在脸上的独眼症或距离过短。 中的所有细胞类型 腹侧神经管发育是Shh信号传导结果， Shh反应中的微小变化可能会对大脑产生微妙的影响。 腹侧细胞类型的形成。 这反过来又可能导致先天性 神经缺陷 已经确定Shh响应是 受响应细胞内的环核苷酸浓度的影响。 增加cAMP浓度会减弱Shh反应，而失去cAMP则会减弱Shh反应。 cAMP依赖性激酶（PKA）激活Shh反应。 这些作者 表明增加cGMP浓度也会增强对 Shh，这表明了一个模型，其中Shh响应取决于循环 反应细胞内的核苷酸浓度，以及环磷酸腺苷和环磷酸鸟苷 对嘘的反应有相反的影响。 存在于该化合物中的几种化合物 环境可以改变细胞内环核苷酸浓度， 通过激活GTP/ATP环化酶， 核苷酸，或通过阻断磷酸二酯酶，降解环 个核苷酸 据推测，环境化合物，改变了 细胞的环核苷酸补体，改变此类细胞中的Shh应答， 导致胚胎畸形从而导致出生缺陷。 假设将 使用鸡胚中Shh反应的敏感测定进行测试。 它 将确定是否环境化合物，改变循环 细胞的核苷酸互补物干扰细胞中正常的Shh信号传导。 在体内发育神经管，或在体外神经外植体中。 在人类中， 暴露于将被测试的化合物是自愿的，如 毛喉素，或非自愿的，像细菌肠毒素，但在任何一种情况下， 关于它们对早期胚胎可能的不利影响知之甚少， 是导致出生缺陷的原因