11β-羟基类固醇脱氢酶长期活性生物标记的研究及应用

发布时间：2018-01-16 16:21

本文关键词：11β-羟基类固醇脱氢酶长期活性生物标记的研究及应用　出处：《东南大学》2017年博士论文　论文类型：学位论文

【摘要】：皮质醇是维持生命的必需糖皮质激素,可的松是皮质醇的主要代谢物。机体循环系统中的皮质醇水平受到下丘脑—垂体—肾上腺皮质(HPA)轴和11β-羟基类固醇脱氢酶(11β-HSD)等多重方式的调节,其中HPA轴主要负责皮质醇的分泌,11β-HSD负责皮质醇的代谢,即皮质醇与可的松之间的相互转化。以往研究常用血液、唾液、尿液基质中皮质醇与可的松的比值(Rbcc,Rscc和Rucc)来评估11β-HSD的长期活性。然而,唾液和尿液生物标记仅能反映即时状态或短期的11β-HSD活性,不能可靠地反映长期的11ββ-HSD活性;而且Rscc和Rucc主要反映唾液腺和肾脏内2型11β-HSD活性,不能反映1型和2型11β-HSD整体活性。尽管Rbcc主要反映机体内11β-HSD整体活性,但不能反映11β-HSD长期活性。值得注意的是,头发皮质醇能够反映HPA轴的长期功能,且其主要来源于血液中游离皮质醇的主动运输或被动扩散。据此推测,头发中R(Rhcc)可能适合用以反映11β-HSD的长期活性和整体活性。因此,本文旨在探索Rhcc作为11β-HSD生物标记的有效性、稳定性和适用性。首先,研究Rhcc作为11β-HSD生物标记的有效性。通过检验头发中类固醇与唾液中类固醇的关联性来验证头发中类固醇的内在生理来源主要为血液中自由类固醇的主动运输或被动扩散。结果发现,头发中类固醇含量和唾液中类固醇含量线性相关显著,这表明血液中自由类固醇的主动运输或被动扩散机制是头发中类固醇的主要内在生理来源。此外,通过检验Rhcc与Rscc的关联性来探索Rhcc反映的11β-HSD整体活性与Rscc反映的唾液腺中11β-HSD2活性之间的关系。结果发现,Rhcc与Rscc线性相关显著,其相关系数小于0.3。这可能是因为Rscc主要反映唾液腺中11β-HSD2的活性,而Rhcc可能反映机体内11β-HSD1和I1β-HSD2的综合活性。其次,研究Rhcc作为11β-HSD生物标记的稳定性。通过前测一后测的追踪研究设计,以单点、单天Rscc和单天Rucc为参照,验证Rhcc的长期稳定性。单点Rscc是反映11β-HSD2活性的急性生物标记,单天Rcc和Rucc是反映11β-HSD2活性的短期生物标记,Rhcc是反映11β-HSD整体活性的长期生物标记。结果发现,单点Rscc在1到2周上的稳定性差;单天Rscc和Rucc在1到2周上具有中等程度的稳定性;Rhcc在6到12个月时间间隔上具有中等程度的稳定性。这些结果表明Rhcc的跨时间相对稳定性优于Rscc和Rucc。最后,通过检验Rhcc能否灵敏地区分四类慢性应激模型人群与正常人群,探索Rh作为11β-HSD长期的回溯性生物标记的适用性。慢性应激模型分别是HPA轴功能异常的慢性心理应激模型(如美沙酮脱毒维持治疗人群)、HPA轴功能正常的慢性持续性心理应激模型(如孤独症患者的照顾者)、HPA轴功能正常的慢性间断性心理应激模型(如A型行为人群),以及HPA轴功能正常的慢性生理应激模型(如肥胖人群)。结果发现,MMT人群、孤独症患者的照顾者和A型行为人群的Rhcc均显著高于对照组,但肥胖人群的Rhcc与对照组无显著性差异。这些结果表明处于慢性心理应激人群的11β-HSD活性可能低下,而处于慢性生理应激人群的11β-HSD活性可能正常。总之,Rhcc可能是能够可靠地反映11β-HSD长期整体活性的、一种新型的、可回溯的生物标记。这将为研究11β-HSD长期活性与慢性应激的关系提供一个新的思路和新的工具。
[Abstract]:Cortisol is a vital essential glucocorticoid, cortisol is the main metabolite of cortisol. Cortisol levels in the circulatory system by the hypothalamus pituitary adrenal (HPA) axis and 11 hydroxysteroid dehydrogenase (11 P -HSD) Regulation of multiple ways, the HPA axis is mainly responsible for the secretion of cortisol, beta 11 -HSD is responsible for the metabolism of cortisol, cortisol and cortisone that is mutual transformation. Previous studies commonly used blood, saliva, urine cortisol and cortisone ratio in the matrix (Rbcc, Rscc and Rucc) to assess the long-term activity of 11 beta -HSD. However, saliva and urine biomarkers can reflect the state of immediate or short-term -HSD beta 11 the activity does not reliably reflect the long-term 11 beta -HSD activity; and Rscc and Rucc mainly reflects the salivary gland and kidney in type 2 -HSD 11 beta activity, cannot reflect the type 1 and type 2 -HSD 11 beta activity. Although Rbc C mainly reflects the body 11 beta -HSD overall activity, but it does not reflect the long-term 11 beta -HSD activity. It is worth noting that hair cortisol can reflect the long-term function of HPA axis, and the main source of free cortisol in the blood active transport or passive diffusion. We speculated that the hair in R (Rhcc) may be used to long term activity and overall activity reflect the 11 beta -HSD. Therefore, this paper aims to explore the validity of Rhcc as 11 beta -HSD biomarkers, stability and applicability. Firstly, study on the validity of Rhcc as 11 beta -HSD biomarkers. Through the empirical analysis on the relationship between hair and saliva steroid steroids to verify the physiological source of hair steroid mainly for active transport of free steroids in the blood or passive diffusion. The results showed that the hair in the linear steroid steroid content content and saliva were significantly related with the blood from that kind of solid Active transport of alcohol or passive diffusion mechanism is the main physiological source of steroids in hair. In addition, to explore the relationship between the activity of -HSD2 11 beta 11 beta -HSD Rhcc reflects the overall activity and Rscc reflected in the salivary glands of the association test of Rhcc and Rscc. The results showed that Rhcc was significantly correlated with the Rscc linear. The correlation coefficient is less than 0.3., this is possible because the Rscc mainly reflects the 11 beta -HSD2 activity in the salivary gland, and Rhcc may reflect the body 11 beta -HSD1 and I1 beta -HSD2 synthesis activity. Secondly, the study of Rhcc as the stability of 11 beta -HSD biomarkers. Through pretest posttest design a follow-up study, to single point single day, single day Rscc and Rucc as the reference, long-term stability verification of Rhcc. Single point Rscc is acute biomarkers reflect 11 beta -HSD2 activity, Rcc and Rucc are single day short-term biomarkers reflect 11 beta -HSD2 activity, Rhcc is the 11 beta -HSD live The long-term biological markers. The results showed that the stability of single point Rscc in 1 to 2 weeks on a single day; Rscc and Rucc in 1 to 2 weeks with a moderate degree of stability; stability of Rhcc is moderate in the 6 to 12 month intervals. These results show that the relative stability is better than the time span Rscc and Rucc. finally Rhcc, by examining whether Rhcc sensitive area crowd of four kinds of models of chronic stress and normal people, explore the applicability of Rh as the 11 beta -HSD retrospective biomarkers. The long-term chronic stress model is the model of chronic psychological stress HPA axis dysfunction (such as methadone maintenance treatment, detoxification group) chronic psychological stress model of HPA axis function (such as autism patients caregivers), chronic intermittent psychological stress model of HPA axis function (such as A, HPA and population) axis function in normal physiology and chronic Ying Jimo Type (such as obesity). The results showed that MMT population, autistic caregivers and type A behavior in Rhcc were significantly higher than control group, but the obesity Rhcc and the control group had no significant difference. These results suggest that chronic psychological stress in the crowd of 11 beta -HSD activity may be low, but in the crowd chronic stress 11 beta -HSD activity may be normal. In conclusion, Rhcc may be able to reliably reflect the overall long-term 11 beta -HSD activity, a new type of biological markers can be back. This will to study the relationship between 11 beta -HSD activity and long-term chronic stress and provide a new idea and new tools.

【学位授予单位】：东南大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R446.1

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