Cardiac Teratogenicity of Lithium

锂的心脏致畸性

• 批准号: 6321654
• 负责人: KERSTI K LINASK
• 金额: $ 32.1万
• 依托单位: UNIV OF MED/DENT NJ-SCH OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6321654
• 关键词: cadherins; cardiotoxin; cell differentiation; chick embryo; congenital heart disorder; developmental genetics; embryo /fetus; embryo /fetus drug adverse effect; embryogenesis; glycogen synthase; heart; histogenesis; laboratory mouse; lithium; microarray technology; phosphorylation; teratogens

DESCRIPTION (Adopted from the Applicant's Abstract): Lithium (Li++) is widely used in the prophylaxis and treatment of bipolar disorder (manic depression) which for women clusters during childbearing years. Controversy continues to exist on the use of lithium during pregnancy and teratogenic effects of during cardiac embryogenesis. Data from lithium birth registries and clinical studies indicate an increased risk in congenital abnormalities with the heart predominantly affected. There have been no cellular and molecular studies addressing lithium's role specifically in cardiac teratogenicity in animal models. Good informative epidemiologic studies among children of women treated with Li++ during pregnancy are difficult to perform. Li++ has been shown to have dramatic effects on morphogenesis in the vertebrate embryo through the Wnt/B-catenin signaling pathway by its inhibition of glycogen synthase kinase-3. How Li++ may exert its teratogenic effects during cardiogenesis is not known. Our research indicates that Li++ affects cytoplasmic 8-catenin in precardiac cells and that these effects are amplified during development. The broad goals are: 1) To determine how Li++ is responsible for the increased incidence of congenital cardiac defects in humans, by analyzing on the cell and molecular level Li++ effects on avian and mouse heart development. 2) Using echocardiography and microarray analyses to determine the effects and pathways by which Li++ acts on the embryonic mouse heart. The hypotheses to be tested are: Hypothesis: Li++ affects cell reorganization into an epithelium and results in wider hearts (2) Hypothesis: Li++ effects on the cardiac compartment are related to its mimicking Wnt signaling and the resulting increased cytoplasmic B-catenin pools. Hypothesis: Elevation of B-catenin by misexpression in the precardiac mesoderm leads to abnormal cardiac cell differentiation and compartmentalization. (2B): Hypothesis: Misexpression of LEF1 inhibits the activation of specific genes that are necessary for subsequent normal cardiac morphogenetic processes to take place. (3) Hypothesis: Li++ exposure in mouse embryos affects cardiac cell function and gene expression. Such studies will provide important insights on a molecular level into the use of Li++ on embryonic human cardiac development during pregnancy. Until the safety of lithium is conclusively proven, one must assume teratogenic potential and harm to the fetus.

描述（从申请人的摘要中采用）：锂（Li ++）广泛 用于预防和治疗躁郁症（躁狂抑郁） 这是女性在生育时期的聚类。争议仍在继续 存在于怀孕期间使用锂和在期间的致畸作用 心脏胚胎发生。来自锂出生注册和临床研究的数据 表明先天性异常的风险增加 主要受到影响。没有细胞和分子研究 针对锂在动物中心脏致伤性方面的作用 型号。受过治疗的妇女儿童的良好信息流行病学研究 怀孕期间的Li ++很难执行。 Li ++已显示为 对脊椎动物胚胎中形态发生具有巨大影响 Wnt/b-catenin信号通路通过糖原合酶的抑制作用 激酶3。 Li ++在心脏病发生期间如何发挥其致畸作用是 不知道。我们的研究表明，li ++会影响细胞质8-catenin par观细胞，并且在发育过程中会放大这些作用。这 广泛的目标是：1）确定Li ++如何负责增加 通过分析细胞和 分子水平LI ++对禽和小鼠心脏发育的影响。 2）使用 超声心动图和微阵列分析以确定效果和途径 Li ++作用于胚胎小鼠心脏。要测试的假设 是：假设：li ++影响细胞重组为上皮和 较宽的心脏（2）假设：LI ++对心脏室的影响 与其模仿Wnt信号有关，并增加 细胞质B-catenin池。假设：B-catenin升高 part级中胚层中的Misexpression导致心脏异常细胞 分化和分隔。 （2b）：假设： LEF1抑制了特定基因的激活 随后发生的正常心脏形态发生过程。 （3） 假设：小鼠胚胎中的Li ++暴露会影响心脏细胞功能和 基因表达。这样的研究将提供有关分子的重要见解 在使用Li ++在胚胎人类心脏发育中的使用水平 怀孕。在最终证明锂的安全之前，必须假设 致化的潜力和对胎儿的伤害。