BRAIN AGING--MOLECULAR EFFECTS OF PERINATAL NUTRITION

脑老化——围产期营养的分子效应

• 批准号: 6299312
• 负责人: JAN Krzysztof BLUSZTAJN
• 金额: $ 22.26万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299312
• 关键词: acetylcholine; age difference; aging; apolipoprotein E; biological signal transduction; choline; cholinergic receptors; developmental genetics; developmental neurobiology; dietary supplements; folate; gene expression; genetically modified animals; in situ hybridization; laboratory mouse; laboratory rat; mother /embryo /fetus nutrition; neurotransmitter metabolism; nutrient bioavailability; nutrition related tag; perinatal; phosphatidylcholines; phosphatidylinositols; phospholipase D; protein kinase

The overall goal of Project 1 is to determine the molecular mechanisms involved in brain reorganization governed by prenatal availability of choline or folic acid and by apolipoprotein E (apoE) genotype. We have found that the availability of choline during the second half of gestation in rats causes biochemical, structural and electrophysiologic changes in brain as well as profound behavioral modifications.. In general, young adult and aged rats supplemented prenatally with choline and improved performance relative to control and prenatally-deficient animals in tasks measuring memory and attention. In contrast,, prenatally deficient animals were impaired in attentional tasks measuring memory and attention. In contrast, prenatally deficient animals were impaired in attentional tasks but somewhat improved in memory tasks. Studies performed to data indicated that prenatal availability of choline may affect the development of multiple synaptic signaling pathways in brain. Specifically prenatal choline availability modifies hippocampal long-term potential,.acetylcholine (ACh) turnover, phospholipase D activity, and indices of nerve growth factor signaling. We will determine the effects of prenatal choline availability and folate availability on signal transduction systems in brain during development, adulthood and aging. Studies performed to date show that prenatal availability of choline alters the patterns of mitosis and apoptosis in developing brain as well as patterns of expression of several proteins. These data are consistent with our hypothesis that prenatal availability of essential nutrients causes multiple changes in brain organization. We propose to determine the developmental patterns of expression of brain genes using hybridization to high density oligonucleotide arrays and reverse Northern analysis followed by in situ hybridization assays of thus identified genes. The metabolism of folate and choline are highly interrelated; therefore the effects of folate availability on ACh turnover in brain will be examined. Within the brain, choline may be redistribut4ed between cells by a mechanism involving apolipoprotein A-mediated transport of a choline- containing lipid. phosphatidylcholine (PC). We will determine if brain ACh turnover is altered in ApoE-/- mice. We will investigate the possibility that dietary choline will modify ACh turnover in folate deficient and ApoE-/- animals. In addition we propose to determine if apoE-containing lipoproteins can supply PC to cholinergic neurons using a cull culture model.

项目 1 的总体目标是确定参与大脑重组的分子机制，该机制受产前胆碱或叶酸的可用性以及载脂蛋白 E (apoE) 基因型的控制。我们发现，在大鼠妊娠后半期，胆碱的可用性会导致大脑的生化、结构和电生理变化，以及深刻的行为改变。一般来说，年轻的成年和老年大鼠在产前补充胆碱，并且相对于对照组和产前缺陷的动物，在测量记忆和注意力的任务中表现得到改善。相比之下，产前缺陷的动物在测量记忆和注意力的注意力任务中受到损害。相比之下，产前缺陷的动物在注意力任务方面受到损害，但在记忆任务方面有所改善。对数据进行的研究表明，产前胆碱的可用性可能会影响大脑中多种突触信号通路的发育。具体来说，产前胆碱的可用性会改变海马的长期潜力、乙酰胆碱 (ACh) 周转、磷脂酶 D 活性和神经生长因子信号传导指数。我们将确定产前胆碱可用性和叶酸可用性对发育、成年和衰老过程中大脑信号转导系统的影响。迄今为止进行的研究表明，产前胆碱的可用性会改变发育中大脑的有丝分裂和细胞凋亡模式以及几种蛋白质的表达模式。这些数据与我们的假设一致，即产前必需营养素的可用性会导致大脑组织发生多种变化。我们建议使用与高密度寡核苷酸阵列杂交和反向Northern分析来确定脑基因表达的发育模式，然后对由此鉴定的基因进行原位杂交测定。叶酸和胆碱的代谢高度相关；因此，将检查叶酸可用性对大脑中乙酰胆碱周转的影响。在大脑内，胆碱可能通过载脂蛋白 A 介导的含胆碱脂质转运机制在细胞之间重新分配。磷脂酰胆碱（PC）。我们将确定 ApoE-/- 小鼠的大脑 ACh 转换是否发生改变。我们将研究膳食胆碱改变叶酸缺乏和 ApoE-/- 动物的 ACh 周转率的可能性。此外，我们建议使用剔除培养模型确定含 apoE 的脂蛋白是否可以向胆碱能神经元提供 PC。