基于计算系统生物学的个体化氨基酸组合方案设计

发布时间：2018-02-20 01:04

本文关键词： 计算系统生物学实体语法系统优化算法作用机理解析个体化氨基酸组合设计　出处：《北京中医药大学》2017年硕士论文　论文类型：学位论文

【摘要】：背景:随着社会经济的高速发展,生活水平的不断提高,现代营养观念已进入一新的时代:人(不一定是患者)应该寻求一种带有普遍性的、基础性的、本质性的营养物质,它适应于疾病状态,也适应于健康状态,尤其适应于现在逐渐被人们认识的、客观存在的亚健康状态。这种营养物质要起到增强体质、加强抗体防御机制、提高生命质量、延缓衰老的非特异性的作用。而氨基酸营养学从必需氨基酸与非必需氨基酸阶段过渡到功能氨基酸阶段,使得氨基酸在预防和治疗代谢疾病包括肥胖、糖尿病、心血管障碍、无乳症胎儿、后天生长迟缓、男女不孕不育、器官功能障碍和疾病感染、增强免疫力、延缓衰老等方面的作用日益凸显,极大地刺激了氨基酸营养品的发展。目的:针对20种标准氨基酸,建立一套个体化的氨基酸营养品配方系统,并能从整体的角度阐释其发挥作用的分子机制,并基于作用机理解析的方法进行组合优化,最终基于医药大数据的平台建立个体化氨基酸组合的半定量设计系统,实现用户通过客户端在线填写关于症状的调查问卷,系统能自动给出相应的氨基酸组合建议。方法:本课题主要通过计算系统生物学的方法来完成。(1)利用实验室较为成熟的实体语法系统,建立针对不同症状的氨基酸营养品配方系统;(2)针对老人、孕妇、儿童等特殊人群,利用贪婪算法和二分图进行氨基酸组合的优化设计;(3)结合网络药理学的方法,以及保健品功能评价标准对氨基酸组合的作用进行作用机理解析;(4)基于作用机理解析的结果对氨基酸组合进行筛选与优化;(5)基于医药大数据平台,建立个体化氨基酸组合的的半定量设计系统,将不同个体的不同症状以及不同症状程度量化,从而实现氨基酸组合的半定量设计。结果:(1)实现了针对1个症状,2个症状,3个症状的氨基酸自动配方系统,充分发挥了氨基酸在人类健康方面的应用;(2)针对老人、孕妇、儿童等特殊人群进行了氨基酸组合设计与优化,从而完善了氨基酸自动配方系统;(3)从网络药理学的角度对氨基酸调节免疫进行了作用机理解析,发现氨基酸及其代谢物调节免疫的分子路径包括:①MAPK信号通路;②Fcε受体信号通路;③NF-κB转录因子活性的正向调控;④内皮细胞生长因子信号通路;⑤TGF-β受体信号通路;⑥T细胞受体信号通路;⑦NO合酶的正向调控;⑧刺激的C型凝集素受体信号通路;⑨ERBB2信号通路;(4)以氨基酸免疫分子网络为背景,以步长为评价指标,建立了免疫强度计算函数Score=∑in=1(∑jn=1fij(L1+L2)),对氨基酸调节免疫的强度进行了计算,最终发现分值排列在前三位的氨基酸为谷氨酸(score:24.67)、酪氨酸(score:20.83)、精氨酸(score:18.05),为氨基酸功能评价提供了新方法,为网络药理学的应用提供了新思路;(5)通过系统打分函数对症状的分析,给出针对不同用户的氨基酸组合推荐,实现了针对不同个体的不同症状以及不同症状程度的个体化氨基酸组合设计。结论:本研究利用计算系统生物学的方法,针对不同人群、不同症状、不同程度进行了个体化的氨基酸组合设计,并通过在线调查问卷的方式,使本研究得到实际应用,为氨基酸营养品的应用奠定了基础。研究中初次探讨了基于分子网络,氨基酸作用强度的评价,有效地减少了传统实验的时间与成本。进一步的研究将对研究结果进行实验证明,优化作用强度函数。
[Abstract]:Background: with the rapid development of social economy, the continuous improvement of living standards, the concept of modern nutrition has entered a new era: people (not necessarily patients) should seek a universal, fundamental, essential nutrients, it adapts to the disease state, but also adapt to the healthy state, especially for now is gradually recognized by people, the objective existence of the sub-health state. This kind of nutrients to enhance physical fitness, strengthen the antibody defense mechanism, improve the quality of life, non-specific anti-aging effect. And the amino acid nutrition from essential amino acid phase transition to the function of amino acids, the amino acids including obesity, diabetes, cardiovascular disorders in the prevention and treatment of metabolic diseases, agalactia fetal, postnatal growth retardation, male infertility, organ dysfunction and disease infection, enhance immunity, delay Aging has become increasingly prominent role, greatly stimulated the development of amino acid supplements. Objective: according to the 20 standard amino acids, amino acid nutrition formula system to establish a set of individual, and from the perspective of the whole play to explain the molecular mechanism of the effect, and based on the combination optimization method based on mechanism analysis, finally semi quantitative design system of medicine of big data platform for the establishment of individual amino acid combination, to achieve the user to fill in a questionnaire about symptoms through the client online system can automatically give the corresponding amino acid combination suggestions. Methods: This study mainly through methods of computational systems biology. (1) the use of laboratory mature entity grammar system according to the established formula system, amino acid nutrition symptoms; (2) for the elderly, pregnant women, children and other special groups, using the greedy algorithm and two points Figure optimized combination of amino acids; (3) combined with the method of network pharmacology, and to evaluate the effect of health care function of the standard amino acid combination mechanism analysis; (4) the mechanism analysis based on the results of amino acid combination screening and optimization; (5) medicine based on big data platform, the establishment of individual amino acid composition the semi quantitative design system, the different symptoms of different individuals and different degree of symptoms quantification, so as to realize the semi quantitative design of amino acid composition. Results: (1) to realize the 1 symptoms, 2 symptoms, automatic amino acid formula system of 3 symptoms, give full play to the use of amino acids in human health.; (2) for the elderly, pregnant women, children and other special groups were designed and optimized to improve the amino acid composition, amino acid automatic dispensing system; (3) Regulation of amino acids from the angle of network pharmacology The mechanism analysis of immunity, including amino acid and its metabolites found the molecular pathways regulating immunity: MAPK signaling pathway; Fc epsilon II receptor signaling pathway; the positive regulation of NF- kappa B transcription factor activity; the endothelial growth factor signaling pathway and TGF- signaling pathway; beta receptor; receptor signaling pathway and T positive cells; the regulation of NO synthase; C type lectin receptor signaling pathway and stimulation; ERBB2 signal pathway; (4) to the amino acid immune molecule network as the background, to step as the evaluation index, the calculation function of Score= in=1 immune strength establishment (sigma jn=1fij (L1+L2)), on the strength of the amino acid regulation of immune the final score calculation, found arranged in the top three of the amino acid glutamic acid (score:24.67), tyrosine (score:20.83), arginine (score:18.05), provides a new method for amino acid functional evaluation, application of network pharmacology Provides a new idea; (5) the symptom analysis system of scoring function, is given for the amino acid composition of different users, to realize the different symptoms of different individuals and different degree of symptoms of individual amino acid combination design. Conclusion: the method of using computational systems biology, for different groups, different symptoms, different the degree of amino acid combination design of individual, and through online questionnaires, this research has been applied, which laid the foundation for the application of amino acid nutrition. Studies are discussed for the first time based on molecular network, evaluation of strength of amino acids, can effectively reduce the time and cost of traditional experiment. Further research will be experimental results prove the optimization function, the intensity function.

【学位授予单位】：北京中医药大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R151

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