本文關鍵詞：11β-羥基類固醇脫氫酶長期活性生物標記的研究及應用　出處：《東南大學》2017年博士論文　論文類型：學位論文

  更多相關文章： 頭發(fā)皮質醇與可的松的比值 11β-羥基類固醇脫氫酶 內在生理來源 穩(wěn)定性 慢性應激

【摘要】：皮質醇是維持生命的必需糖皮質激素,可的松是皮質醇的主要代謝物。機體循環(huán)系統(tǒng)中的皮質醇水平受到下丘腦—垂體—腎上腺皮質(HPA)軸和11β-羥基類固醇脫氫酶(11β-HSD)等多重方式的調節(jié),其中HPA軸主要負責皮質醇的分泌,11β-HSD負責皮質醇的代謝,即皮質醇與可的松之間的相互轉化。以往研究常用血液、唾液、尿液基質中皮質醇與可的松的比值(Rbcc,Rscc和Rucc)來評估11β-HSD的長期活性。然而,唾液和尿液生物標記僅能反映即時狀態(tài)或短期的11β-HSD活性,不能可靠地反映長期的11ββ-HSD活性;而且Rscc和Rucc主要反映唾液腺和腎臟內2型11β-HSD活性,不能反映1型和2型11β-HSD整體活性。盡管Rbcc主要反映機體內11β-HSD整體活性,但不能反映11β-HSD長期活性。值得注意的是,頭發(fā)皮質醇能夠反映HPA軸的長期功能,且其主要來源于血液中游離皮質醇的主動運輸或被動擴散。據(jù)此推測,頭發(fā)中R(Rhcc)可能適合用以反映11β-HSD的長期活性和整體活性。因此,本文旨在探索Rhcc作為11β-HSD生物標記的有效性、穩(wěn)定性和適用性。首先,研究Rhcc作為11β-HSD生物標記的有效性。通過檢驗頭發(fā)中類固醇與唾液中類固醇的關聯(lián)性來驗證頭發(fā)中類固醇的內在生理來源主要為血液中自由類固醇的主動運輸或被動擴散。結果發(fā)現(xiàn),頭發(fā)中類固醇含量和唾液中類固醇含量線性相關顯著,這表明血液中自由類固醇的主動運輸或被動擴散機制是頭發(fā)中類固醇的主要內在生理來源。此外,通過檢驗Rhcc與Rscc的關聯(lián)性來探索Rhcc反映的11β-HSD整體活性與Rscc反映的唾液腺中11β-HSD2活性之間的關系。結果發(fā)現(xiàn),Rhcc與Rscc線性相關顯著,其相關系數(shù)小于0.3。這可能是因為Rscc主要反映唾液腺中11β-HSD2的活性,而Rhcc可能反映機體內11β-HSD1和I1β-HSD2的綜合活性。其次,研究Rhcc作為11β-HSD生物標記的穩(wěn)定性。通過前測一后測的追蹤研究設計,以單點、單天Rscc和單天Rucc為參照,驗證Rhcc的長期穩(wěn)定性。單點Rscc是反映11β-HSD2活性的急性生物標記,單天Rcc和Rucc是反映11β-HSD2活性的短期生物標記,Rhcc是反映11β-HSD整體活性的長期生物標記。結果發(fā)現(xiàn),單點Rscc在1到2周上的穩(wěn)定性差;單天Rscc和Rucc在1到2周上具有中等程度的穩(wěn)定性;Rhcc在6到12個月時間間隔上具有中等程度的穩(wěn)定性。這些結果表明Rhcc的跨時間相對穩(wěn)定性優(yōu)于Rscc和Rucc。最后,通過檢驗Rhcc能否靈敏地區(qū)分四類慢性應激模型人群與正常人群,探索Rh作為11β-HSD長期的回溯性生物標記的適用性。慢性應激模型分別是HPA軸功能異常的慢性心理應激模型(如美沙酮脫毒維持治療人群)、HPA軸功能正常的慢性持續(xù)性心理應激模型(如孤獨癥患者的照顧者)、HPA軸功能正常的慢性間斷性心理應激模型(如A型行為人群),以及HPA軸功能正常的慢性生理應激模型(如肥胖人群)。結果發(fā)現(xiàn),MMT人群、孤獨癥患者的照顧者和A型行為人群的Rhcc均顯著高于對照組,但肥胖人群的Rhcc與對照組無顯著性差異。這些結果表明處于慢性心理應激人群的11β-HSD活性可能低下,而處于慢性生理應激人群的11β-HSD活性可能正常�？傊�,Rhcc可能是能夠可靠地反映11β-HSD長期整體活性的、一種新型的、可回溯的生物標記。這將為研究11β-HSD長期活性與慢性應激的關系提供一個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.

【學位授予單位】：東南大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R446.1

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