Testing Direct Effects of Soy Daidzein on Fragile X Phenotypes

描述(由申请人提供)： 这个项目探索了未经检验的假设，即大豆植物雌激素大豆苷元会加剧脆性X综合征(FXS)的表型。FXS是最常见的遗传性智力残疾形式。我们实验室的偶然发现表明，以大豆为基础的饮食增加了FXS小鼠模型、Fmr1KO小鼠以及后来被诊断为自闭症的婴儿的癫痫发生率。在小鼠研究中，大豆中的一种促进癫痫的成分被鉴定为大豆植物雌激素大豆苷元。我们假设，出生后发育期间以大豆为基础的饮食会加剧多种FXS表型。这项拨款申请是一项初步研究，目的是确定大豆苷元及其代谢物在WT和Fmr1KO小鼠体内的药代动力学，以及它们对癫痫阈值、焦虑、多动和感觉运动门控等FXS表型的影响。成功的实验结果将为RO1拨款申请提供初步数据，以测试Fmr1KO小鼠对无大豆饮食的额外FXS表型的拯救以及潜在的分子机制。该项目的长期目标是在Fmr1KO小鼠身上提供坚实的临床前数据，支持限制以大豆为基础的婴儿配方奶粉用于患有FXS和其他神经发育障碍的婴儿。

DESCRIPTION (provided by applicant): This project explores the untested hypothesis that the soy phytoestrogen daidzein exacerbates fragile X syndrome (FXS) phenotypes. FXS is the most common form of inherited intellectual disability. Serendipitous findings from our laboratory indicate that a soy-based diet increases seizure incidence in a mouse model of FXS, Fmr1KO mice, as well as in infants later diagnosed with autism. In the mouse studies, a seizure-promoting ingredient in the soy was identified as the soy phytoestrogen daidzein. We hypothesize that a soy-based diet during postnatal development exacerbates multiple FXS phenotypes. This grant application is a pilot study to determine the pharmacokinetics of daidzein and its metabolites in WT and Fmr1KO mice as well as their effects on well-established FXS phenotypes including seizure threshold, anxiety, hyperactivity and sensorimotor gating. Successful experimental outcomes will provide the preliminary data for an RO1 grant application to test the rescue of additional FXS phenotypes in Fmr1KO mice in response to a soy-free diet as well as the underlying molecular mechanism. The long-term goal of this project is provide solid pre-clinical data in Fmr1KO mice that support the restriction of soy-based infant formulas for babies with FXS and other neurodevelopmental disorders.