CATECHOLAMINES AND DEVELOPMENT

儿茶酚胺与开发

• 批准号: 6539896
• 负责人: SUZANNE Katherine ROFFLER-TARLOV
• 金额: $ 27.07万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-26 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6539896
• 关键词: catecholamines; corpus striatum; developmental neurobiology; dopamine; embryo /fetus cell /tissue; embryonic stem cell; enzyme activity; gene deletion mutation; gene targeting; genetically modified animals; laboratory mouse; neurogenetics; norepinephrine; phenotype; sweat glands; tyrosine 3 monooxygenase

DESCRIPTION (Adapted from the applicant's abstract): This proposal examines the hypothesis that: (1) catecholamines (dopamine and norepinephrine) have role in development that precedes neurotransmitter function and that (2) catecholamines are made in the absence of tyrosine hydroxylase (TH) through the activity of tyrosinase, the enzyme that catalyzes the synthesis of melanin pigments. The studies will focus on two newly created mutations: a tyrosine hydroxylase (TH)-depleted mouse on a pigmented background that the investigator made through homologous recombination in embryonic stem cells and TH depleted mouse on a tyrosinase -deficient background. Both mutations are embryonic lethal conditions. Neither type of TH-null embryo displays glyoxylic acid induced fluorescence indicating that catecholamines are absent. Both types of TH-null mice can be rescued in utero with a variety of agents and they live for several weeks after birth without further treatment. It was expected that the original TH-null pups would contain no catecholamines because TH is essential for synthesis. However, the original TH-null, which is on a pigmented background, does display glyoxylic acid induced fluorescence indicating the presence of catecholamines postnatally. In contrast, the tyrosinase-deficient TH-null pups do not have histofluorescence. This indicates that tyrosinase, which like TH uses tyrosine as a substrate may supply catecholamines in these extraordinary circumstances. Using histological and biochemical techniques, it is planned to learn whether catechol or other amines are formed in the TH-null untreated embryos and rescued pups and whether they are a consequence of tyrosinase activity. It is intended to uncover the fate of neurons that in a normal animal would contain catecholamines. Finally, the rescued TH-null tyrosinase-deficient mice will be used to study two developmental events in which catecholamines may participate as regulators of development. The investigator will examine pattern formation in the striatum to test the hypothesis that reciprocal interactions of dopamine and its targets regulate the development of the striatal mosaic. They will test the hypothesis that norepinephrine induces the differentiation factor that directs the switch from an adrenergic to a cholinergic phenotype in sympathetically-innervated sweat glands.

描述（改编自申请人的摘要）：该提案审查了 假设：（1）儿茶酚胺（多巴胺和去甲肾上腺素）在 先于神经递质功能的发育，并且 (2) 儿茶酚胺 是在没有酪氨酸羟化酶（TH）的情况下通过以下活性制成的 酪氨酸酶，催化黑色素合成的酶。这 研究将集中在两个新创建的突变上：酪氨酸羟化酶 研究人员制作的色素背景上的 (TH) 耗尽的小鼠 通过胚胎干细胞和 TH 耗尽的小鼠中的同源重组 在酪氨酸酶缺乏的背景下。两种突变都是胚胎致死的 状况。两种类型的 TH 缺失胚胎均未表现出乙醛酸诱导的 荧光表明不存在儿茶酚胺。两种类型的 TH-null 可以用多种药物在子宫内拯救小鼠，并且它们可以存活数年 出生后几周无需进一步治疗。原本以为是 TH 缺失的幼崽将不含儿茶酚胺，因为 TH 对于 合成。然而，原始的 TH-null 位于有色背景上， 确实显示出乙醛酸诱导的荧光，表明存在 产后儿茶酚胺。相比之下，酪氨酸酶缺陷的 TH-null 幼崽 没有组织荧光。这表明酪氨酸酶，如 TH 使用酪氨酸作为底物可以在这些非凡的作用中提供儿茶酚胺 情况。计划利用组织学和生化技术 了解未处理的 TH-null 中是否形成儿茶酚或其他胺 胚胎和获救的幼崽以及它们是否是酪氨酸酶的结果 活动。它的目的是揭示正常动物神经元的命运 会含有儿茶酚胺。最后，拯救了 TH-null 酪氨酸酶缺陷型 小鼠将被用于研究儿茶酚胺可能影响的两个发育事件 作为发展的监管者参与。调查员将检查模式 纹状体中的形成，以检验相互相互作用的假设 多巴胺及其靶标调节纹状体嵌合体的发育。 他们将检验去甲肾上腺素诱导分化的假设 指导从肾上腺素能表型转变为胆碱能表型的因子 受交感神经支配的汗腺。

项目成果

Catecholamines are required for the acquisition of secretory responsiveness by sweat glands.

儿茶酚胺是汗腺获得分泌反应性所必需的。

• DOI: 10.1523/jneurosci.20-19-07362.2000
• 发表时间: 2000
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Tian,H;Habecker,B;Guidry,G;Gurtan,A;Rios,M;Roffler-Tarlov,S;Landis,SC
• 通讯作者: Landis,SC