GENETIC ANALYSIS OF NEUROTRANSMITTER RECEPTORS IN AGING

衰老过程中神经递质受体的遗传分析

• 批准号: 6299396
• 负责人: JOAN M LAKOSKI
• 金额: $ 17.67万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299396
• 关键词: age difference; aging; autoradiography; binding sites; brain mapping; brain stem; dopamine transporter; genetic markers; in situ hybridization; laboratory mouse; neurochemistry; neuropharmacology; northern blottings; phenotype; prosencephalon; quantitative trait loci; receptor binding; receptor expression; serotonin receptor; serotonin transporter

Aging processes in mammalian species include significant age-related changes in central nervous system function with changes in neurotransmitter receptors as an etiology common to normal and pathological disorders of aging, including Alzheimer's disease. The role of serotonin (5-hydroxytryptamine; 5-HT) neurotransmission in aging has demonstrated an age-related decline of multiple 5-HT selective receptor subtypes and the 5-HT transporter in forebrain and brainstem regions, including the frontal cortex, hippocampus and dorsal raphe nucleus. To date, the cellular and molecular characteristics of diverse serotonergic binding sites across the lifespan have not been correlated with relevant genetic markers. Additionally, the role of dopamine neurotransmission, specifically the dopamine transporter, while demonstrated to decline with aging, has yet to be correlated with relevant genetic markers. Therefore, these studies will address the neuropharmacology of multiple 5-HT receptors as well as the 5-HT and DA transporters to test the hypothesis that age-related decline in central receptor function correlates with genetic based variability in these neurotransmitter systems. Cellular and molecular biological techniques will assess gender-specific changes in multiple 5-HT receptor subtypes and compare the 5-HT and DA transporters in a panel of BXD recombinant inbred mice and their progenitor strains with respect to age (150, 450 and 750 days). Genetic analysis will subsequently be performed in order to locate chromosomal regions containing the quantitative trait loci (QTL) which effect these receptors. Ultimately, pairing of QTL analysis with the neuropharmacologic characterization of central serotonin and dopamine binding sites in selected brain regions, will permit both the sequencing of genes and the identification of specific products of these genes involved in ventral nervous system aging.

哺乳动物物种的衰老过程包括显著的年龄相关 中枢神经系统功能的变化 神经递质受体作为一种常见的病因 病理性衰老障碍，包括阿尔茨海默病。角色 5-羟色胺(5-羟色胺；5-羟色胺)神经递质在衰老中的作用 多个5-羟色胺选择性受体的年龄相关性下降 前脑和脑干区的亚型和5-羟色胺转运体， 包括额叶皮质、海马体和中缝背核。至 DATE，不同5-羟色胺能细胞和分子特征 在整个生命周期内，结合位点与相关的 遗传标记。此外，多巴胺的神经传递作用， 特别是多巴胺转运蛋白，虽然显示出下降 随着年龄的增长，尚未与相关的遗传标记相关联。 因此，这些研究将针对多发性硬化的神经药理学。 5-羟色胺受体以及5-羟色胺和多巴胺转运体 中枢受体功能随年龄增长而下降的假说 与这些神经递质的遗传变异性相关 系统。 细胞和分子生物学技术将评估特定性别 多种5-羟色胺受体亚型的变化及与多巴胺的比较 BXD重组近交系小鼠及其转运蛋白的研究 与日龄有关的祖代菌株(150、450和750天)。遗传 随后将进行分析以定位染色体 包含影响这些基因的数量性状基因座(QTL)的区域 感受器。最终，QTL分析与 中枢5-羟色胺和多巴胺的神经药理学特征 在选定的大脑区域中的结合位点，将允许测序 以及这些基因的特定产物的鉴定 与腹侧神经系统老化有关。