基于D-氨基酸集合轮廓的阿尔茨海默病诊断和治疗效果评价模型的研究

Alzheimer's disease (AD) is one of the diseases that seriously endanger the health of the elderly. Its symptoms come on insidiously and progress rather slowly. The degenerative process in AD probably starts even 20 to 30 years before the clinical onset of the disease. Consequently, early recognition and diagnosis of AD are of great significance and have been the focus of medical domain at home and abroad. D-amino acids are endogenous substances in human and play many important biological roles which are involved in the incidence and process of AD. Alterations in the concentrations of D-amino acids have also been found between healthy persons and AD patients. These suggested that D-amino acids will be a new kind of biomarker for AD which may not only be helpful in the diagnostic process, but also provide novel therapeutic targets. In this research, the method of targeted metabolomics will be applied to study the correlations between the concentration alterations of D-amino acids and AD. Methods of multivariate statistical analysis will be adopted to find the novel biomarkers for AD and develop the mathematical modeling for diagnose based on D-amino acids profiling. And then the evaluations of drug treatment effects on AD will be carried out by the use of newly developed modeling, combined with ethology and pharmacology. Finally, pathogenesis of AD will be explored with molecular pathology. As D-amino acids being the target molecules, the related metabolic network and regulatory pathways will be investigated. The project will provide theoretical and practical support for establishing new diagnostic method, efficient drug evaluating approach and revealing molecular mechanisms of pathogenesis for AD.

阿尔茨海默病（AD）是一种严重危害老年人健康的疾病，其起病隐匿、进展缓慢，病理改变早在症状出现前20～30 年就已产生，因此AD的早期识别与诊断意义重大，一直是国内外医学领域研究的重点和难点。内源性物质D-氨基酸的多种生理作用与AD发生发展关系密切，而且其浓度水平在正常人与AD患者体内存在显著差异，为AD的诊断和治疗提供了新的线索和思路。本课题拟采用目标性代谢组学的研究方法，寻找新型特异性D-氨基酸类生物标记物，结合多元统计分析方法，建立基于D-氨基酸集合轮廓的AD诊断新模型；采用D-氨基酸集合轮廓法，对药物治疗AD效果进行评价，结合行为学和病理学结果，对方法的科学性进行检验；以D-氨基酸自身为靶标，研究相关代谢网络和调控途径，探讨AD发病的分子机理。本课题的实施必将为建立科学的AD早期诊断新方法、有效的药物治疗AD效果评价手段和揭示AD发病的分子机理提供理论和实践依据。

阿尔茨海默病（AD）是一种严重危害老年人健康的疾病，其早期识别与诊断意义重大。内源性物质D-氨基酸的多种生理作用与AD发生发展关系密切，而且其浓度水平在正常人与AD患者体内存在显著差异，为AD的诊断和治疗提供了新的线索和思路。. （1）本课题以体内特定的代谢物D-氨基酸为研究切入点，建立了灵敏、高效的非手性衍生化法与手性固定相高效液相色谱-质谱联用法，手性衍生化法与非手性固定相高效液相色谱-质谱联用法，实现生物样品中多种痕量D-氨基酸分子的同时测定；. （2）采用目标性代谢组学的研究方法，利用已建立的方法分别测定健康组和AD组血浆、尿液中D-氨基酸的含量，运用多元统计方法确定了多种AD特异性D-氨基酸类生物标记物，建立了与AD相关的D-氨基酸集合轮廓，作为AD预测诊断的新模型；. （3）采用D-氨基酸集合轮廓法对治疗AD疗效确切的胆碱脂酶抑制剂石杉碱甲和中药材文官果壳进行药物治疗效果评价；. （4）采用分子病理学的研究方法，分析测定健康大鼠和AD大鼠海马、皮层、嗅球、小脑中D-氨基酸的含量，确定了不同区域脑组织中含量发生显著变化的D-氨基酸分子；以含量发生变化的D-氨基酸为靶标，结合不同区域脑组织的功能特点，研究相关代谢网络和调控途径，探讨AD发病机理，并且进一步说明基于D-氨基酸集合轮廓法的AD新型诊断模型的科学性。. 本项目研究发现了AD特异性D-氨基酸类生物标记物，建立了基于D-氨基酸集合轮廓的AD预测诊断和治疗药物评价新模型，探讨了AD的发病机理，为AD早期诊断、治疗和作用机理研究提供了理论和实践依据。. 在项目进行期间，发表学术论文6篇，其中SCI收载3篇，获沈阳市自然学术成果二等奖1项；培养硕士研究生2名；参加国内外学术会议5次，做大会报告2次。