Diethanolamine, brain development and adult memory

二乙醇胺，大脑发育和成人记忆

• 批准号: 6877989
• 负责人: Steven H Zeisel
• 金额: $ 14.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877989
• 关键词: amygdala; apoptosis; biomarker; cell proliferation; cerebellum; cerebral cortex; choline; choline deficiency; dementia; developmental neurobiology; dietary supplements; disease /disorder model; disease /disorder proneness /risk; embryo /fetus cell /tissue; embryo /fetus toxicology; environmental exposure; ethanolamines; hippocampus; immunocytochemistry; laboratory mouse; memory; mother /embryo /fetus nutrition; neurogenesis; skin absorption; stem cells

DESCRIPTION (provided by applicant): In this proposal we will examine how diethanolamine (DEA) effects the development of the hippocampus in the fetal mouse, and thereby could alter the onset of diminished memory function (senile dementia) in later adult life. DEA is used in the synthesis of fatty acid condensates that are present in many consumer products, including shampoos and cosmetics. DEA is structurally similar to choline, a methyl donor and an important endogenous precursor in the synthesis of phospholipids and acetylcholine. DEA competes with choline for tissue uptake and incorporation into phospholipids and mice treated with DEA become choline deficient. Maternal dietary choline intake during late pregnancy modulates mitosis and apoptosis in progenitor cells of the fetal hippocampus and septum and alters the differentiation of neurons in fetal hippocampus and causes significant and irreversible changes in hippocampal function in the adult animal, including altered long term potentiation and altered memory. We propose to test the hypotheses that exposure to DEA during pregnancy diminishes progenitor cell proliferation and increases apoptosis in the fetal hippocampus in a manner similar to that which we previously described in choline deficiency. If the hypothesis is confirmed, it would be possible to propose extensive studies on the structural, biochemical and functional effects of DEA on brain development and its effects on memory. The specific aims of the proposal are 1) Determine whether DEA applied dermally to the pregnant mouse dam alters progenitor cell proliferation and apoptosis in the embryonic mouse hippocampus; 2) Determine whether DEA induced changes noted in Aim 1 can be prevented by choline supplementation and 3) Determine whether DEA induces changes in brain regions other than the hippocampus. Our proposal meets all required elements of PAR-03-121 including: sound mechanistic foundation for fetal programming of adult memory function; study of an environmental agent DEA to which there is known significant human exposure; use of gene expression profiling in fetus and adult; specific adult onset disease (senile dementia); and a focus on a required emphasis area (brain/nervous system); demonstrated expertise in developmental biology/toxicology and disease pathophysiology and gene expression profiling.

描述（由申请人提供）：在此提案中，我们将研究二乙醇胺（DEA）如何影响胎儿小鼠中海马的发展，从而可以改变后来的成人生活中记忆功能降低（老年痴呆）的开始。 DEA用于许多消费产品（包括洗发水和化妆品）中存在的脂肪酸冷凝物的合成。 DEA在结构上类似于胆碱，甲基供体和重要的内源性前体，用于合成磷脂和乙酰胆碱。 DEA与胆碱竞争组织吸收，并掺入磷脂中，用DEA治疗的小鼠会胆碱缺乏。孕妇妊娠晚期孕妇饮食胆碱的摄入可调节胎儿海马和隔膜的祖细胞的有丝分裂和凋亡，并改变胎儿海马中神经元的分化，并在成年动物（包括长期久期的长期增强和改变的成年动物）中的海马功能发生显着且不可逆转的变化。我们建议测试怀孕期间暴露于DEA的假设减少祖细胞的增殖，并以类似于我们先前在胆碱缺乏症中描述的方式增加胎儿海马的凋亡。如果确认该假设，就可以提出有关DEA对脑发育及其对记忆作用的结构，生化和功能影响的广泛研究。该提案的具体目的是1）确定DEA是否在孕妇小鼠海马中的祖细胞的增殖和凋亡会改变真皮。 2）确定AIM 1中DEA诱导的变化是否可以通过补充胆碱来预防和3）确定DEA是否诱导海马以外的其他大脑区域变化。我们的建议符合PAR-03-121的所有必需要素，包括：成人记忆功能的胎儿编程的声音机械基础；研究已知人类暴露的环境药物DEA；在胎儿和成人中使用基因表达分析；特定的成人发作疾病（老年痴呆症）；并关注所需的重点区域（大脑/神经系统）；在发育生物学/毒理学和疾病病理生理学和基因表达分析方面具有专业知识。