【摘要】： 端粒的縮短限制了人類細(xì)胞的分裂增殖，因此它常見于人類組織器官的衰老過程中。在第四代端粒酶敲除小鼠中，端粒功能的缺陷致使組織器官功能受損，壽命縮短。然而，端粒功能缺陷在人類衰老和疾病中的作用目前仍存在很大的爭議。我們研究發(fā)現(xiàn)了一組蛋白質(zhì)：CRAMP、EF-1α、Chitinase 3L3、Stathmin。這組蛋白質(zhì)在老年端粒酶敲除小鼠的多個器官(如肝臟、腎臟、脾臟、心臟、肺、大腦等)和血清中異常高表達，但是在老年野生型端粒功能正常的小鼠中沒有相似的高表達發(fā)現(xiàn)。我們還發(fā)現(xiàn)，這組人類的同源蛋白質(zhì)在人類衰老過程中高表達于血清以及其他的器官中(如肝臟、脾臟等)。而且在端粒縮短相關(guān)疾病中呈過度表達(如肝臟纖維化、骨髓發(fā)育不良綜合征等)。我們將進一步研究這組蛋白質(zhì)與腎臟疾病的關(guān)系，探索其作用機制。 端粒位于染色體末端防止由于DNA損傷激活導(dǎo)致得細(xì)胞衰老或者凋亡。已經(jīng)有確鑿的證據(jù)表明端粒縮短會導(dǎo)致人類衰老和慢性疾病的發(fā)生。且同時發(fā)現(xiàn)端粒酶基因的突變會導(dǎo)致端粒的縮短，組織器官修復(fù)功能的損傷，以及人類和小鼠壽命的縮短。雖然大量的遺傳學(xué)和臨床實驗證明端�？s短導(dǎo)致組織器官修復(fù)功能的損傷和壽命的縮短。然而，在端粒功能缺陷導(dǎo)致人類壽命縮短和疾病的機制方面仍然存在不同的爭議。在人類和某些靈長類動物的衰老過程中，皮膚會有大量衰老細(xì)胞累積，，但在其他例如肌肉或者肝臟等器官中并未發(fā)現(xiàn)此類衰老細(xì)胞累積現(xiàn)象。在衰老的端粒酶敲除小鼠中，端粒功能的缺陷還與干細(xì)胞功能的損傷相關(guān)，并導(dǎo)致器官修復(fù)功能受損以及壽命縮短。然而在這種端粒酶敲除小鼠模型體內(nèi)并沒有發(fā)現(xiàn)衰老細(xì)胞的累積現(xiàn)象。在這種模型小鼠體內(nèi)發(fā)現(xiàn)衰老的細(xì)胞被凋亡和免疫反應(yīng)清除。顯然衰老是受到細(xì)胞周期調(diào)控的。因此端粒功能缺陷在衰老過程中的作用可以通過對衰老細(xì)胞的實驗研究來證實。而衰老的臨床生物學(xué)信號的研究與發(fā)現(xiàn)，對于衰老的研究領(lǐng)域更是具有劃時代的挑戰(zhàn)意義。 在人類細(xì)胞的體外培養(yǎng)實驗研究中發(fā)現(xiàn)端粒功能低水平缺陷就可以誘導(dǎo)細(xì)胞衰老。因此如果我們能夠發(fā)現(xiàn)鑒定一組蛋白質(zhì)生物學(xué)信號，它們可以在細(xì)胞衰老前期或者疾病早期就反應(yīng)細(xì)胞體內(nèi)的端粒功能水平的底下和DNA損傷，那么將對人類衰老和某些衰老相關(guān)疾病的研究產(chǎn)生重要的影響。由于全球都面臨老齡化這一重要問題，人口老齡化所帶來的一系列相關(guān)疾病問題，這一組蛋白質(zhì)生物學(xué)信號的發(fā)現(xiàn)與鑒定無疑將對此意義深遠。 我們的實驗發(fā)現(xiàn)第四代端粒酶敲除小鼠(G4mTerc~(-/-))并沒有呈現(xiàn)衰老細(xì)胞體內(nèi)累積現(xiàn)象，但是其衰老表型仍然與端粒功能缺陷密切相關(guān)。我們有充分理由相信這種小鼠模型能夠為發(fā)現(xiàn)和鑒定端粒功能缺陷誘導(dǎo)衰老前期細(xì)胞分泌的蛋白質(zhì)提供完善的實驗體系。而好的臨床信號應(yīng)當(dāng)能夠易于通過體液檢測到。因此，我們的實驗設(shè)計體外短時間培養(yǎng)(4小時)2月和12月齡的第四代端粒酶敲除小鼠以及端粒功能正常野生型小鼠的骨髓細(xì)胞，收集其培養(yǎng)液，通過蛋白質(zhì)組學(xué)實驗方法(CE-TOF-MS)鑒別不同的蛋白質(zhì)組分泌。然后通過統(tǒng)計學(xué)方法建立能夠鑒別這四組不同實驗小鼠的蛋白質(zhì)組模型(suppl．Fig．1a-e)。 然后我們通過質(zhì)譜技術(shù)測序鑒定了一組4個蛋白質(zhì)。他們在12月齡的第四代端粒酶敲除小鼠中異常高表達，顯著區(qū)別于其他三組小鼠(n=5／組，figure 1a)。我們還設(shè)計了一個單盲實驗來檢驗這組蛋白質(zhì)模型。四組共計26只小鼠用于單盲檢測，敏感度為91％，特異性為60％。這四組小鼠骨髓細(xì)胞蛋白質(zhì)Western blot結(jié)果進一步證實這組蛋白質(zhì)在12月齡的第四代端粒酶敲除小鼠中異常高表達(figure1b)。 測序結(jié)果發(fā)現(xiàn)這組蛋白質(zhì)為：1，CRAMP-它在免疫反應(yīng)早期被激活，保護機體免受細(xì)菌引起的感染侵?jǐn)_。2，Chitinase 3 like protein 3(Chi3L3)-它屬于chitinase家族，也在免疫反應(yīng)早期被激活，已經(jīng)有實驗證實它與軟骨細(xì)胞的衰老和關(guān)節(jié)炎相關(guān)。3，Elongation factor1α(EF-1α)，它與蛋白質(zhì)的合成密切相關(guān)，也在人類纖維細(xì)胞的衰老中表達增加。4，Stathmin(OP18)，它與微小管的穩(wěn)定結(jié)構(gòu)，細(xì)胞活性和有絲分裂密切相關(guān)(25)。 我們同時檢測了實驗小鼠(2月和12月齡的第四代端粒酶敲除小鼠以及端粒功能正常野生型小鼠，24月齡端粒功能正常野生型小鼠)的心臟、肝臟、腎臟、大腦、脾臟和肺臟等組織器官這組蛋白質(zhì)信號的mRNA水平表達的高低(figure 1c)。發(fā)現(xiàn)CRAMP和Chi3L3在所有12月齡第四代端粒酶敲除小鼠檢測器官mRNA水平均為高表達，而EF-1α和Stathmin則表現(xiàn)出器官特異性，僅在12月齡第四代端粒酶敲除小鼠心臟和肺臟中高表達。免疫熒光進一步證實這組蛋白質(zhì)信號在12月齡第四代端粒酶敲除小鼠臟器中特異性高表達(figure 1d，Suppl．Table 1，Suppl．Fig．2)。在實驗小鼠血清ELISA檢測中我們也發(fā)現(xiàn)了這組蛋白質(zhì)信號在12月齡第四代端粒酶敲除小鼠體內(nèi)的高表達(Figure 1e)。CRAMP和Chi3L3在24月齡端粒功能正常野生型小鼠血清中還呈現(xiàn)中等量的高表達，但是并沒有在12月齡的24月齡端粒功能正常野生型小鼠體內(nèi)表達量高。這組蛋白質(zhì)信號在老齡的生長激素基因缺陷小鼠體內(nèi)并沒有高表達(Suppl．Fig．3a-d)。這一結(jié)果說明這組蛋白質(zhì)信號僅與端粒功能缺陷小鼠的衰老相關(guān)。 由于人類還未發(fā)現(xiàn)與小鼠Chi3L3相似同源蛋白質(zhì)，因此我們檢測體內(nèi)chitinase酶的活性來反應(yīng)人類衰老和疾病過程中chitinase的變化。我們選用體外培養(yǎng)30代、40代、50代、60代和70代的人類纖維細(xì)胞進行體外實驗，其中60代細(xì)胞是衰老前期細(xì)胞，70代的細(xì)胞已經(jīng)是衰老的細(xì)胞了。mRNA水平蛋白質(zhì)水平檢測均發(fā)現(xiàn)60代和70代的細(xì)胞CRAMP、EF-1α、stathimin呈現(xiàn)顯著高表達(figure3a，b)。對細(xì)胞培養(yǎng)液的ELISA檢測均發(fā)現(xiàn)60代和70代的細(xì)胞CRAMP、EF-1α、stathimin和chitinase酶活性呈現(xiàn)顯著高表達(figure3c-e)。這組實驗結(jié)果揭示這組蛋白質(zhì)信號亦與人類細(xì)胞端粒功能缺陷和DNA損傷相關(guān)。 我們進一步進行人類衰老和疾病組的體外檢測。發(fā)現(xiàn)這組蛋白質(zhì)信號在健康老年人體內(nèi)顯著高表達與健康年輕人，在疾病老年人則表現(xiàn)為進一步的高表達(figure2a-d)。揭示這組蛋白質(zhì)信號在人類血清中的表達與人類的衰老和疾病密切相關(guān)。多因素回歸統(tǒng)計分析結(jié)果顯示CRAMP和chitinase酶活性是其中作用最強的2個信號，將這二個蛋白質(zhì)信號進行加權(quán)統(tǒng)計，可以更好的鑒別健康年輕組、健康老年組和疾病老年組(figure2e)。我們還和傳統(tǒng)的衰老信號IL-6~(26-28)進行比較，發(fā)現(xiàn)我們的這組蛋白質(zhì)信號比IL-6具有更高的敏感度和特異性(figure2f)。免疫熒光進一步證實這些蛋白質(zhì)信號在老年器官中的高表達(Suppl．Fig．4,Suppl．Table2)。 有很多人類疾病與端粒縮短相關(guān)，例如肝臟纖維化，是慢性肝臟疾病終末期功能衰竭的標(biāo)志。纖維化患者肝臟組織的這組蛋白質(zhì)信號mRNA表達顯著高與未纖維化患者(figure3f)。血清ELISA結(jié)果辦顯示纖維化患者這組蛋白質(zhì)信號表達顯著高與未纖維化患者(figure4g-k)。免疫熒光進一步顯示纖維化患者肝臟組織這組蛋白質(zhì)信號的顯著高表達(figure4a)． 骨髓增生不良綜合征MDS是另一種與端粒縮短導(dǎo)致造血干細(xì)胞和骨髓細(xì)胞功能衰竭相關(guān)的疾病~(29)。MDS患者血清中這組蛋白質(zhì)信號表達明顯高于健康對照組(figure4b-f)。 IgA腎病也是一種與端�？s短相關(guān)的疾病。我們的實驗發(fā)現(xiàn)這組蛋白質(zhì)信號的表達與IgA腎病的進展相關(guān)，血清ELISA結(jié)果明確顯示(figure5)，免疫熒光進一步證實結(jié)果(figure5d-g)。 綜上所述，本研究從衰老的端粒酶敲除小鼠體內(nèi)發(fā)現(xiàn)了一組四個特異性的蛋白質(zhì)。他們與非端�？s短功能異常所致的衰老無關(guān)。本研究還發(fā)現(xiàn)這組蛋白質(zhì)信號不僅僅是端粒缺陷小鼠的衰老信號，還是人類衰老和疾病的信號。說明了端粒的縮短在人類衰老和疾病的過程中的重要作用。 這些由于端粒功能缺陷說所釋放的蛋白質(zhì)不僅僅是人類衰老的生物學(xué)信號，還預(yù)示著在衰老和慢性疾病過程中細(xì)胞和組織器官的損壞、功能的異常。已有的文獻報道證明，端粒功能異常的間質(zhì)細(xì)胞會影響臨近的腫瘤細(xì)胞或者造血干細(xì)胞功能。CRAMP和Chitinase已經(jīng)被證實與感染性疾病和免疫應(yīng)答相關(guān)。免疫應(yīng)答的啟動在衰老所致的心血管疾病中起到重要作用。已有的文獻報道也證實了端粒的縮短和功能缺陷能夠激活免疫應(yīng)答，這可以在一定程度上幫助我們理解人類衰老過程中的易感狀態(tài)。
[Abstract]:Telomere shortening limits the division and proliferation of human cells, so it is common in the aging process of human tissues and organs. In the fourth generation of telomerase knockout mice, telomere dysfunction impairs tissue and organ function and shortens life span. However, the role of telomere dysfunction in human aging and disease remains controversial. We found a group of proteins: CRAMP, EF-1a, Chitinase 3L3, Stathmin. These proteins were abnormally high in many organs (such as liver, kidney, spleen, heart, lung, brain, etc.) and serum of aged telomerase-knockout mice, but no similar high expression was found in aged wild-type telomere-functioning mice. We also found that this group of human homologous proteins is highly expressed in serum and other organs (such as liver, spleen, etc.) during human aging, and is overexpressed in telomere shortening-related diseases (such as liver fibrosis, myelodysplastic syndrome, etc.). We will further study the relationship between this group of proteins and kidney diseases. To explore the mechanism of action.
Telomeres are located at the end of chromosomes to prevent cell senescence or apoptosis due to activation of DNA damage. Confirmed evidence has shown that telomere shortening leads to aging and chronic diseases in humans. Despite numerous genetic and clinical studies that have shown that telomere shortening causes damage to tissue and organ repair and shortens life span, there are still disputes about the mechanisms by which telomere dysfunction leads to shortened life span and disease in humans and in some primates. In aging telomerase knockout mice, defective telomere function is also associated with damage to stem cell function, resulting in impaired organ repair and shortened life span. Aging is apparently regulated by the cell cycle. Therefore, the role of telomere dysfunction in the aging process can be confirmed by experimental studies on aging cells. The research and discovery of physical signals is of epoch-making significance in the field of aging research.
So if we can identify a set of proteomic signals that can reflect the level of telomere function and DNA damage in cells at the early stages of cell senescence or disease, then The discovery and identification of this group of protein biological signals will undoubtedly be of far-reaching significance to the study of human aging and some aging-related diseases.
Our experiment found that the fourth generation of telomerase knockout mice (G4mTerc ~(-/-)) did not show in vivo accumulation of aging cells, but their aging phenotype is still closely related to telomere dysfunction. Quality provides a complete experimental system, and good clinical signals should be easily detected by body fluids. Therefore, our experimental design is to culture bone marrow cells of 2nd and 12th generation telomerase knockout mice and wild type mice with normal telomere function in vitro for a short period of time (4 hours), and collect their culture medium through proteomic experiments. Methods CE-TOF-MS was used to identify the secretion of different proteomes, and then a proteomic model (suppl.Fig.1a-e) was established to identify these four groups of mice.
Then we sequenced a group of four proteins by mass spectrometry. They were overexpressed in the fourth generation of 12-month-old telomerase knockout mice, significantly different from the other three groups of mice (n=5/group, figure 1a). We also designed a single-blind experiment to test the protein model. A total of 26 mice in the four groups were used for single-blind detection. The sensitivity and specificity were 91% and 60% respectively. Western blot results of bone marrow cell proteins from these four groups of mice further confirmed the abnormally high expression of these proteins (figure 1b) in the fourth generation of 12-month-old telomerase knockout mice.
Sequencing results showed that this group of proteins is: 1, CRAMP - it is activated in the early immune response to protect the body from infection caused by bacteria. 2, Chitinase 3 like protein 3 (Chi3L3) - it belongs to the chitinase family, is also activated in the early immune response, has been proved to be associated with chondrocyte aging and arthritis. 3, Elongat Iofactor1alpha (EF-1alpha), which is closely related to protein synthesis, is also increased in the aging of human fibroblasts. 4, Stathmin (OP18), which is closely related to the stable structure of microtubules, cell activity and mitosis (25).
We also examined the expression of protein signaling mRNA (figure 1c) in heart, liver, kidney, brain, spleen and lung of experimental mice (2nd and 12th generation telomerase knockout mice and wild type mice with normal telomere function, and wild type mice with normal telomere function at 24th month old). Both Chi3L3 and EF-1a were highly expressed in the detectors of all 12-month-old fourth-generation telomerase knockout mice, while EF-1a and Stathmin were organ-specific, and only overexpressed in the heart and lungs of 12-month-old fourth-generation telomerase knockout mice. High specific expression (figure 1d, Suppl. Table 1, Suppl. Fig. 2) was also found in the serum of 12-month-old fourth generation telomerase knockout mice (Figure 1e). CRAMP and Chi3L3 also appeared in the serum of 24-month-old wild type mice with normal telomere function. Moderately overexpressed, but not overexpressed in 12-month-old wild-type mice with normal telomere function at 24 months of age. This protein signal was not overexpressed in the aged mice with growth hormone deficiency (Suppl. Fig. 3a-d). This result suggests that this protein signal is only associated with the aging of mice with telomere deficiency. Relevant.
Since no homologous protein has been found to be similar to mouse Chi3L3, we tested the activity of chitinase in vivo to reflect the changes of chitinase during human aging and disease. The expression of CRAMP, EF-1a and stathimin was significantly higher in both 60 and 70 generations of cells (figure 3a, b). The activity of CRAMP, EF-1a, stathimin and chitinase was significantly higher in 60 and 70 generations of cells (figure 3c-e) by ELISA. These results reveal that this protein signal is also related to telomere dysfunction and DNA damage in human cells.
We further examined the human aging and disease group in vitro. We found that these proteins were highly expressed in healthy old people and healthy young people, but further high expressed in disease old people (figure 2a-d). Correlation. Multivariate regression analysis showed that CRAMP and chitinase activity were the two strongest signals. Weighted statistics of these two protein signals could better differentiate the healthy young group, the healthy old group and the sick old group (figure 2e). We also compared them with the traditional aging signal IL-6~ (26-28) and found that CRAMP and chitinase activity were the two strongest signals. Our set of protein signals are more sensitive and specific than IL-6 (figure 2f). Immunofluorescence further confirms the high expression of these protein signals in older organs (Suppl.Fig.4, Suppl.Table2).
There are many human diseases associated with telomere shortening, such as liver fibrosis, which is a marker of end-stage failure in chronic liver disease. This group of protein signaling mRNA expression in fibrotic liver tissue is significantly higher than that in non-fibrotic liver tissue (figure 3f). Serum ELISA results show that this group of protein signaling expression in fibrotic patients is significantly higher than that in non-fibrotic liver tissue. Immunofluorescence further demonstrated a significant overexpression of this group of protein signals (figure 4a) in fibrotic liver tissue.
Myelodysplastic syndrome (MDS) is another disease associated with telomere shortening leading to hematopoietic stem cell and bone marrow cell failure.
IgA nephropathy is also a disease associated with telomere shortening. Our experiments found that the expression of these proteins was associated with the progression of IgA nephropathy. The serum ELISA results clearly showed (figure 5), and immunofluorescence further confirmed the results (figure 5d-g).
In summary, this study found four specific proteins in aging telomerase knockout mice. They were not associated with aging caused by abnormal telomere shortening. This study also found that these proteins are not only aging signals in telomere-deficient mice, but also signals of aging and disease in humans. The important role of shortening in the process of human aging and disease.
These proteins released by telomere dysfunction theory are not only biological signals of aging in humans, but also indicate damage to cells and tissues and organs during aging and chronic diseases, and dysfunction. Previous reports have shown that telomere dysfunctional stromal cells affect adjacent tumor cells or hematopoietic stem cells. Cellular function. CRAMP and Chitinase have been shown to be associated with infectious diseases and immune responses. Initiation of the immune response plays an important role in cardiovascular diseases caused by aging. The susceptible state of aging.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2008
【分類號】：R363

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