本文選題：銀屑病 + IMQ誘導的小鼠模型��； 參考：《第二軍醫(yī)大學》2017年博士論文

【摘要】：銀屑病是一種自發(fā)性的自身免疫性疾病,影響著約全球約2%的人口,在中國發(fā)病率稍低,但中國人口基數(shù)龐大,有著約500-800萬的銀屑病患者。由于銀屑病目前還不能根治,且特別容易復發(fā),給患者身心及家庭帶來了嚴重的損害。咪喹莫特(imiquimod,IMQ)最初用于治療人皮膚癌和外生殖器/肛周疣等疾病,后被研究者開發(fā)并用在小鼠皮膚上來誘導銀屑病樣的癥狀。由于該模型能很好的誘導出人銀屑病的絕大部分癥狀,且模型簡單易制備,迅速成為研究銀屑病的一個重要模型。過氧化物酶體增殖物激活受體(peroxisome proliferator-activated receptors,PPARs)屬于II型核受體超家族,可分為3種亞型(PPARα/γ/δ)。PPARδ在代謝綜合征、動脈粥樣硬化、脂代謝紊亂等疾病過程中發(fā)揮了重要的作用。前期的實驗發(fā)現(xiàn)PPARδ在人銀屑病皮損和IMQ誘導的小鼠銀屑病皮膚中高表達,提示其可能在銀屑病的發(fā)生發(fā)展中起到一定的作用。目前銀屑病的治療沒有很好的辦法,且不能徹底的治愈,本實驗借助IMQ誘導的銀屑病樣小鼠以及人角質(zhì)原代細胞進行一系列實驗,為PPARδ在銀屑病中的作用提供更為有力和直接的證據(jù),以期為銀屑病的治療提供新的治療靶點。第一部分PPARδ在銀屑病皮損中的表達情況目的:為了考察PPARδ在人和小鼠銀屑病皮損及正常皮膚中的表達情況,從而為PPARδ在銀屑病中的作用提供依據(jù)。方法:取健康人皮膚和銀屑病人皮損處皮膚,小鼠正常皮膚和IMQ刺激后的皮膚,進行免疫組織化學(immunohistochemistry,IHC)、實時熒光定量PCR(quantitative polymerase chain reaction,Q-PCR)和蛋白免疫印跡(Western Blot,WB)實驗,考察PPARδ在正常皮膚和銀屑病皮損中、表皮和真皮層中的表達差異。并進一步探討了PPARδ在銀屑病皮損部位的特異性表達。結(jié)果:人銀屑病皮損和小鼠經(jīng)IMQ刺激皮膚中的PPARδ表達較健康皮膚和正常小鼠皮膚均升高。通過IHC染色觀察到,人皮損處的PPARδ主要表達于表皮上基底層。真皮、表皮的表達偏好來看,人及小鼠皮膚中PPARδ主要表達于表皮層,而真皮層中含量很少。PPARδ于健康人皮膚中表達很少,同時也很少表達于其它幾種皮膚疾病的皮損中,表明了PPARδ在銀屑病皮損部位表達的相對特異性。結(jié)論:PPARδ在人銀屑病皮損處及IMQ誘導的小鼠銀屑病皮損中有所升高,表明了PPARδ很可能在銀屑病的發(fā)病中起到了很重要的作用。第二部分PPARδ對于原代角質(zhì)細胞體外分泌細胞因子的作用目的:考察PPARδ在不同細胞炎癥模型中所起的作用及其潛在機制。本部分我們一共借助了三類比較常規(guī)的與銀屑病關(guān)系比較密切的細胞模型。(1)白介素(interleukin,IL)-17、IL-22和腫瘤壞死因子alpha(tumor necrosis factor,TNF-α)等細胞因子在銀屑病的發(fā)展中起到重要的作用,我們探尋了PPARδ對于在這些細胞因子作用下角質(zhì)細胞炎癥反應(yīng)的影響。(2)12-O-十四烷酰佛波醋酸酯-13(12-O-Tetradecanoylphorbol-13-acetate,TPA)在體內(nèi)也常用于誘導小鼠的銀屑病樣模型,且有報道稱TPA能有到小鼠皮膚中PPARδ表達的上調(diào),在體外實驗中TPA常被用于誘導原代角質(zhì)細胞的分化,我們預在本實驗中考察PPARδ是否也對TPA作用的原代角質(zhì)起到一定的調(diào)控作用。(3)IMQ乳膏溶液作用于角質(zhì)細胞是最近被研究者開發(fā)并使用的一個銀屑病細胞模型,能夠更進一步的反應(yīng)銀屑病角質(zhì)細胞的病理情況,我們預考察PPARδ在該體外細胞模型中所起到的作用。方法:本實驗成功提取了人原代角質(zhì)細胞,并分別成功構(gòu)建了三種角質(zhì)細胞炎癥模型。利用Q-PCR、WB等方法考察了PPARδ選擇性激動劑GW0742和專一性拮抗劑GSK3787在這些模型中對炎癥的影響,并進一步考察了PPARδ在這一過程中的作用機制。結(jié)果:(1)通過實驗在眾多的PPARδ響應(yīng)基因中確定了改變最大的一個基因:脂質(zhì)分化相關(guān)蛋白(Adipose differentiation-related protein,ADRP),并以它作為后續(xù)實驗中考察PPARδ是否激活的一個指標;(2)PPARδ激動劑GW0742能加劇IL-17A、IL-22或TNF-α誘導的原代角質(zhì)細胞炎癥情況;(3)TPA誘導的原代角質(zhì)細胞炎癥情況不依賴于PPARδ通路,但我們發(fā)現(xiàn)TPA+GW0742能共同激活人黑素瘤缺乏因子2(Absent in Melanoma 2,AIM-2)的表達,而最近有報道稱AIM-2在銀屑病的發(fā)展中占有一定的作用。(4)PPARδ抑制劑能緩解IMQ誘導的原代角質(zhì)細胞炎癥情況;結(jié)論:本部分實驗在細胞模型上驗證了PPARδ在銀屑病相關(guān)炎癥方面的作用,首先PPARδ的拮抗劑能降低IL-17、IL-22或TNF-α誘導的炎癥因子的分泌。TPA誘導的原代角質(zhì)細胞炎癥雖然不依賴于PPARδ,但是當TPA和PPARδ的激動劑同時存在時,AIM-2的表達被上調(diào),這說明PPARδ還能在一定的程度上激活一些通路來協(xié)同其它的刺激因素產(chǎn)生其原來所沒有的作用,PPARδ的這一現(xiàn)象也與之前報道的其能調(diào)控豐富的下游基因的功能相一致。此外,IMQ誘導的原代角質(zhì)細胞炎癥能夠被PPARδ的激動劑加強,同時能被PPARδ的抑制劑減弱。第三部分PPARδ在體內(nèi)銀屑病樣小鼠模型中的作用及其機制研究目的:前面實驗表明PPARδ對于IMQ誘導的原代細胞炎癥起到了一定的作用,且PPARδ在銀屑病皮損處高表達,為了考察PPARδ在體內(nèi)銀屑病小鼠模型中的作用及其作用機制,設(shè)計這一部分實驗。方法:首先配制PPARδ的體內(nèi)注射溶液,在IMQ刺激前2 h、刺激后4 h、8 h注射入小鼠皮下,空白組用PBS代替注射。連續(xù)6天后,處死小鼠取材,皮膚均分為4份,一份檢測Q-PCR,一份檢測WB,一份檢測IHC,一份用作流式細胞術(shù)檢測使用。通過HE染色、IHC染色、Q-PCR、流式細胞術(shù)(Flow Cytometry,FCM)等技術(shù),我們觀察了小鼠皮膚的病理情況并檢測了小鼠皮膚中銀屑病相關(guān)炎癥因子及炎癥細胞的變化情況。對于PPARδ作用機制的研究,我們將不同組的小鼠皮膚提取蛋白,進行WB實驗,篩選信號通路。結(jié)果:PPARδ專一性拮抗劑GSK3787能下調(diào)IMQ引起的表皮棘層肥厚現(xiàn)象,同時從HE的結(jié)果上看,真皮層的浸潤細胞也有所降低。GSK3787還能降低IMQ引起的IL-17a、IL-23、IL-22和IL-1b等的表達升高,并且GSK3787的這些作用呈濃度和時間依賴性。此外,TCRβ+IL-17A+及TCRγδ+IL-17A+(T17+)細胞在IMQ+GSK組也較IMQ組有所下調(diào)。對于PPARδ在IMQ模型中作用機制的研究,我們發(fā)現(xiàn)PI3K-AKT及STAT3信號通路在模型組小鼠皮損中表達上調(diào),我們進一步注射該通路蛋白的抑制劑,發(fā)現(xiàn)PPARδ的作用被減弱。結(jié)論:PPARδ拮抗劑能夠緩解IMQ引起的銀屑病樣皮損癥狀,且能降低銀屑病相關(guān)炎癥因子及炎癥細胞的表達,提示其可能作為一種潛在的銀屑病治療新靶點。IMQ誘導的銀屑病樣小鼠皮膚炎癥中,PPARδ是通過PI3K-AKT及STAT3通路來發(fā)揮作用的。第四部分阻斷Alox8能減輕IMQ在小鼠皮膚上引起的銀屑病樣反應(yīng)目的:之前的實驗中已經(jīng)較為深入地探明了PPARδ在銀屑病發(fā)病中的作用,但是PPARδ的內(nèi)源性配體還不是很明確。雖然我們在第一部分中闡明,Alox8/8s-HETE是PPARδ潛在的上游配體中表達最高的一對,且有相關(guān)研究表明,Alox8/8s-HETE可能在皮膚炎癥性疾病的發(fā)生中起到一定的作用。但是它們是否真的在體內(nèi)對PPARδ有這調(diào)控的作用我們還不能肯定,為了進一步考察PPARδ的上游配體Alox8對于PPARδ的潛在調(diào)控作用,進行了以下實驗。方法:目前由于沒有市售的PPARδ中和性抗體,為了方便Alox8體內(nèi)的阻斷,我們構(gòu)建了慢病毒包裝的Alox8 sh RNA干擾序列。我們首先考察了用Alox8 sh RNA干擾后,利用Q-PCR實驗方法測量了PPARδ各響應(yīng)基因的激活情況并用免疫共沉淀的方法考察了PPARδ與RXRa結(jié)合情況的變化。隨后,我們又進一步利用Q-PCR法、WB法和FCM的方法考察了Alox8 sh RNA干擾后,小鼠皮膚中總體炎癥情況的改變以及銀屑病相關(guān)炎癥蛋白表達的變化以及炎癥細胞數(shù)量的改變。結(jié)果:體內(nèi)Alox8 sh RNA干擾后,Alox8蛋白的表達量較陰性對照序列有所下降,此外,小鼠皮膚內(nèi)PPARδ各響應(yīng)基因的表達均下調(diào),其中以ADRP的表達下降的最多,與體外實驗的趨勢相近。Alox8的干擾還使得小鼠皮膚中的總體炎癥情況有所緩解。最后Alox8 sh RNA-IMQ小鼠皮膚中的銀屑病相關(guān)炎癥蛋白的表達和炎癥細胞的浸潤都較IMQ模型組中有所減少。結(jié)論:以上實驗結(jié)果表明,Alox8是PPARδ在銀屑病發(fā)病中發(fā)揮重要作用的關(guān)鍵性配體。對Alox8的干擾不僅能阻斷PPARδ的作用,且沒有發(fā)現(xiàn)明顯的不良反應(yīng),表明Alox8對于PPARδ的作用可能比較單一,是銀屑病治療的另一個潛在的治療靶點。
[Abstract]:Psoriasis is a spontaneous autoimmune disease that affects about 2% of the population around the world and has a low incidence in China, but China has a large population base, with about 500-800 million patients with psoriasis. As psoriasis is not yet radical, and it is especially easy to relapse, it has caused serious damage to the patients and their families. Im Iquimod, IMQ) was originally used to treat human skin cancer and external genital / perianal warts and other diseases, which were developed and used to induce psoriasis like symptoms in the skin of mice. The model can induce most of the symptoms of psoriasis, and the model is easy to be prepared and quickly become an important model for the study of psoriasis. The peroxisome proliferator activated receptor (peroxisome proliferator-activated receptors, PPARs) belongs to the II type nuclear receptor superfamily, and can be divided into 3 subtypes (PPAR alpha / gamma / delta).PPAR Delta in the metabolic syndrome, atherosclerosis, lipid metabolism disorder and other diseases. Previous experiments found PPAR Delta in human psoriasis. The high expression of skin lesions and IMQ induced psoriasis in mice suggests that it may play a role in the development of psoriasis. At present, the treatment of psoriasis is not very good and can not be cured thoroughly. This experiment was conducted with the aid of IMQ induced psoriasis like mice and human keratinocytes for a series of experiments for PPAR Delta. The role of psoriasis provides more powerful and direct evidence to provide new therapeutic targets for the treatment of psoriasis. Part 1 the expression of PPAR Delta in psoriatic lesions: To investigate the expression of PPAR Delta in the skin and skin of psoriasis in humans and mice and to provide the role of PPAR Delta in psoriasis. Methods: the skin, normal skin and IMQ stimulated skin of healthy skin and silver chip patients, immunohistochemistry (IHC), real-time fluorescent quantitative PCR (quantitative polymerase chain reaction, Q-PCR) and protein immunoblotting (Western Blot, WB) experiment were carried out to investigate the normal skin and the normal skin. The expression difference in epidermis and dermis in psoriatic lesions and the specific expression of PPAR Delta in the skin lesions of psoriasis. Results: the expression of PPAR Delta in the skin lesions of human psoriasis and IMQ stimulated skin in mice was higher than that in healthy skin and normal mice. The main table of PPAR Delta in human skin lesions was observed by IHC staining. The expression of PPAR Delta in human and mouse skin is mainly expressed in the epidermis, while the content of.PPAR Delta in the dermis is rarely expressed in the skin of the healthy human skin, and it is also rarely expressed in the skin lesions of several other skin diseases, indicating the relative specificity of PPAR delta expressed in the skin lesions of psoriasis. Conclusion: PPAR Delta in psoriasis and IMQ induced psoriasis in the skin lesions of mice, indicating that PPAR delta may play an important role in the pathogenesis of psoriasis. Second part of the function of PPAR Delta for the secretion of cytokine in the primary keratinocytes in vitro: investigation of PPAR Delta in different cellular inflammatory models In this part, we have used three types of cell models that are more closely related to psoriasis. (1) cytokines such as interleukin (IL) -17, IL-22 and tumor necrosis factor alpha (tumor necrosis factor, TNF- a) play an important role in the development of psoriasis, we have explored the PP. The effect of AR Delta on the inflammatory response of keratinocytes under the action of these cytokines. (2) 12-O- fourteen alkyl acetate -13 (12-O-Tetradecanoylphorbol-13-acetate, TPA) is also used to induce psoriasis like model in mice in vivo, and it is reported that TPA can increase the expression of PPAR Delta in mouse skin, and TPA often in vitro. It is used to induce differentiation of primary keratinocytes. In this experiment, we investigate whether PPAR delta may also play a role in regulating the primary horniness of TPA. (3) the IMQ cream solution acts on keratinocytes as a psoriatic cell model developed and used recently by researchers to further respond to psoriatic keratinocytes. We previewed the role of PPAR Delta in this extracorporeal cell model. Methods: the human primary keratinocytes were successfully extracted and three keratinocytes were successfully constructed. The PPAR delta selective agonist GW0742 and the exclusive antagonist GSK3787 were investigated by Q-PCR, WB and other methods. The effect of PPAR Delta on this process was further investigated. Results: (1) the largest one was identified by the experiment in many PPAR delta response genes: the Adipose differentiation-related protein (ADRP), and it was used as a follow-up to investigate whether the PPAR delta was activated. One index: (2) PPAR delta agonist GW0742 can aggravate primary keratinocyte inflammation induced by IL-17A, IL-22 or TNF- alpha; (3) TPA induced primary keratinocyte inflammation does not depend on the PPAR delta pathway, but we found that TPA+GW0742 can co activate the expression of human melanoma deficiency factor 2 (Absent in Melanoma 2, AIM-2), and recently reported It is known that AIM-2 plays a role in the development of psoriasis. (4) PPAR delta inhibitors can relieve IMQ induced primary keratinocyte inflammation. Conclusion: this part of this experiment demonstrated the role of PPAR Delta in psoriasis related inflammation. First, PPAR delta antagonists can reduce the inflammatory factors induced by IL-17, IL-22 or TNF- alpha. The secretion of.TPA induced primary keratinocytes is not dependent on PPAR Delta, but when the activator of TPA and PPAR delta exists simultaneously, the expression of AIM-2 is up-regulated, indicating that PPAR delta can also activate some pathways to produce its original role in conjunction with other stimuli. This phenomenon of PPAR delta is also the same as before. It is reported that it can regulate the functions of the rich downstream genes. In addition, IMQ induced primary keratinocyte inflammation can be enhanced by PPAR delta agonists and can be weakened by the inhibitor of PPAR Delta. The role and mechanism of the third part of PPAR Delta in the mice model of psoriasis like mice and its mechanism: the previous experiment showed that PPAR delta was lured to IMQ. The primary cell inflammation plays a certain role, and PPAR delta is highly expressed in the skin lesions of psoriasis. In order to investigate the role and mechanism of PPAR Delta in the mice model of psoriasis in vivo, this part of the experiment was designed. Method: first, the injection solution of PPAR delta was prepared in vivo, 2 h before IMQ stimulation, 4 h after stimulation, and 8 h injection into the subcutaneous of mice. The blank group replaced the injection with PBS for 6 days. The mice were sacrificed for 6 days. The skin was divided into 4 parts, one was Q-PCR, one was tested for WB, one was IHC, and one was used for flow cytometry. We observed the pathology of the skin of mice by HE staining, IHC staining, Q-PCR, flow cytometry (Flow Cytometry, FCM) and other techniques. The changes of inflammatory factors and inflammatory cells related to psoriasis in the skin of mice. For the study of the mechanism of PPAR delta action, we extracted protein from different groups of mice, carried out WB experiments and screened signal pathways. Results: the PPAR delta specific antagonist GSK3787 could downregulate the hypertrophy of the epidermal spinous layer caused by IMQ and the result of HE. In the dermis, the infiltrating cells of the dermis also reduced.GSK3787 and decreased the expression of IL-17a, IL-23, IL-22 and IL-1b caused by IMQ, and the effects of GSK3787 were concentration and time dependent. Furthermore, TCR beta +IL-17A+ and TCR gamma +IL-17A+ (T17+) cells were also down down in the group. We found that the PI3K-AKT and STAT3 signaling pathways were up-regulated in the skin lesions of the model mice. We further injected the inhibitor of this pathway protein and found that the effect of PPAR delta was weakened. Conclusion: PPAR delta antagonists can relieve the symptoms of psoriasis like skin lesions caused by IMQ and reduce the inflammatory factors associated with psoriasis and the fine inflammation. Cell expression, suggesting that PPAR delta may play a role in the skin inflammation of psoriasis like mice induced by.IMQ, a new target for psoriasis treatment. The fourth blocking of Alox8 can alleviate the psoriasis like response to IMQ in the skin of mice: the previous experiments have been more thorough. The role of PPAR Delta in the pathogenesis of psoriasis is explored, but the endogenous ligands of PPAR delta are not very clear. Although we have stated in the first part that Alox8/8s-HETE is the highest expression of the PPAR delta potential upstream ligand, the relevant studies suggest that Alox8/8s-HETE may play a certain role in the occurrence of inflammatory diseases of the skin. But we are not sure whether they really play a role in the regulation of PPAR Delta in the body. In order to further investigate the potential regulation of the upstream ligand of PPAR Delta, Alox8 for PPAR Delta, the following experiments are carried out. Method: we are currently constructing the PPAR delta neutralization anti body, in order to facilitate the blocking of Alox8 in the body. The Alox8 sh RNA interference sequence of the lentivirus package. We first examined the Alox8 sh RNA interference and measured the activation of each response gene of PPAR Delta using the Q-PCR experimental method and examined the changes in the combination of PPAR Delta and RXRa with the method of immunoprecipitation. After the interference of Alox8 sh RNA, the overall inflammation in the skin of mice and the changes in the expression of inflammatory proteins related to psoriasis and the changes in the number of inflammatory cells. Results: after the interference of Alox8 sh RNA in the body, the expression of Alox8 protein decreased more than that of the negative control sequence. In addition, the expression of the PPAR delta response genes in the skin of the mice was all lower. The expression of ADRP decreased most, and the.Alox8 interference with the trend of in vitro experiments also made the overall inflammation in the skin of the mice relieved. Finally, the expression of inflammatory proteins related to psoriasis and the infiltration of inflammatory cells in the skin of Alox8 sh RNA-IMQ mice were less than those in the IMQ model group. The results show that Alox8 is the key ligand for PPAR delta to play an important role in the pathogenesis of psoriasis. The interference with Alox8 not only blocks the effect of PPAR Delta, but also does not find obvious adverse reactions. It indicates that the effect of Alox8 on PPAR delta may be relatively single, and it is another potential therapeutic target for the treatment of psoriasis.

【學位授予單位】：第二軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R758.63

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9 葉平;過氧化體增殖物激活型受體(PPAR)與心血管疾病[J];中華心血管病雜志;2004年07期

10 孫曙光,周智廣;PPARγ與1型糖尿病[J];國外醫(yī)學.內(nèi)分泌學分冊;2005年02期

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1 ;Genetic polymorphisms of PPAR-γ,HHEX,PTPRD,KCNQ1,and SRR affect therapeutic efficacy of Pioglitazone in Chinese Patients with type 2 diabetes[A];傳承與發(fā)展，，創(chuàng)湖南省生理科學事業(yè)的新高——湖南省生理科學會2011年度學術(shù)年會論文摘要匯編[C];2011年

2 ;Dynamic analysis and ligand binding affinity investigation of PPAR mutations[A];華東六省一市生物化學與分子生物學會2003年學術(shù)交流會論文摘要集[C];2003年

3 童南偉;;過氧化物酶增殖物激活受體(PPAR)a與脂質(zhì)代謝[A];全國首屆代謝綜合征的基礎(chǔ)與臨床專題學術(shù)會議論文匯編[C];2004年

4 王偉銘;章慧娣;劉峰;陳佳韻;陳楠;;PPARγ活化對腎間質(zhì)成纖維細胞的作用研究[A];2007年浙滬兩地腎臟病學術(shù)年會資料匯編[C];2007年

5 陳剛;林新富;梁繼興;林麗香;沈曉麗;;過氧化物酶體增殖物激活受體γ(PPARγ)基因多態(tài)性與老年男性骨質(zhì)疏松癥相關(guān)性研究[A];2008內(nèi)分泌代謝性疾病系列研討會暨中青年英文論壇論文匯編[C];2008年

6 陳剛;林新富;梁繼興;林麗香;沈曉麗;;過氧化物酶體增殖物激活受體γ(PPARγ)基因多態(tài)性與老年男性骨質(zhì)疏松癥相關(guān)性研究[A];2008中國醫(yī)師協(xié)會內(nèi)分泌代謝科醫(yī)師分會年會論文匯編[C];2008年

7 李潔;戴愛國;胡瑞成;朱黎明;王梅芳;;PPARγ影響γ-谷氨酰半胱氨酸合成酶活性及表達在大鼠慢性阻塞性肺疾病中的作用[A];中國生理學會第23屆全國會員代表大會暨生理學學術(shù)大會論文摘要文集[C];2010年

8 管又飛;;脂質(zhì)過氧化物體增殖物激活受體γ(PPAR γ)與糖尿病腎病[A];中華醫(yī)學會腎臟學分會2004年年會暨第二屆全國中青年腎臟病學術(shù)會議專題講座匯編[C];2004年

9 孫莉;尚進林;梁浩;程焱;;PPAR全激動劑對小鼠局灶性腦缺血再灌注損傷的保護作用[A];第十一屆全國神經(jīng)病學學術(shù)會議論文匯編[C];2008年

10 ;Endothelial PPARγmediates anti-inflammatory actions of rosiglitazone through dissociation of NF-κB[A];中國生理學會心血管生理學術(shù)研討會論文集[C];2011年

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1 徐錚奎;發(fā)現(xiàn)PPAR拮抗劑[N];醫(yī)藥經(jīng)濟報;2012年

2 曾凡新邋林敏;PPAR激動劑類抗糖尿病藥研發(fā)喜憂參半[N];中國醫(yī)藥報;2007年

3 袁松范;開發(fā)PPAR多通道激動劑須謹慎[N];中國醫(yī)藥報;2006年

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2 陳宏;巨噬細胞PPARγ對皮膚傷口愈合的作用研究[D];第三軍醫(yī)大學;2015年

3 韓晶;PPARγ在腦缺血再灌注損傷和過氧化氫損傷中的調(diào)控機制研究[D];天津醫(yī)科大學;2014年

4 張鷗;阿托伐他汀對動脈粥樣硬化患者外周血中PPAR γ的作用研究及相關(guān)炎癥因子與動脈粥樣硬化關(guān)系的建模分析[D];鄭州大學;2016年

5 周毅;PPARγ介導的抗氧化機制在血管平滑肌細胞表型轉(zhuǎn)化中作用和機制研究[D];第三軍醫(yī)大學;2016年

6 滕志朋;PPARβ/δ在大鼠蛛網(wǎng)膜下腔出血后早期腦損傷中的作用及其機制研究[D];重慶醫(yī)科大學;2016年

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8 張花治;紅芪多糖對db/db小鼠糖尿病心肌病心肌保護作用及PPARγ/NF-κB信號通路的影響[D];甘肅中醫(yī)藥大學;2017年

9 任凌云;T細胞PPARγ在心臟移植慢性排反應(yīng)中的作用及機制研究[D];華中科技大學;2016年

10 王學魁;PPARδ基因增加乳腺癌細胞在惡劣代謝環(huán)境中生存率的研究[D];吉林大學;2017年

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1 曹智麗;過氧化物酶增殖物激活受體α（PPARα）在大鼠酒精性肝病發(fā)生過程中的變化[D];河北醫(yī)科大學;2015年

2 宋石;miR-27a通過靶向調(diào)控PPARγ對酒精誘導大鼠BMSC分化的影響[D];鄭州大學;2015年

3 鄒佳楠;PPAR-γ在IgA腎病發(fā)生中的作用及其機理研究[D];復旦大學;2014年

4 陶曉燕;PPAR δ激動劑和siRNA對大鼠骨髓基質(zhì)干細胞及成骨細胞分化和礦化的作用研究[D];安徽醫(yī)科大學;2015年

5 于飛;新型PPARγ激動劑對人腎癌細胞增殖抑制及其機制的研究[D];中國人民解放軍軍事醫(yī)學科學院;2015年

6 何修界;PPARγ激活對GDM小鼠胎盤脂肪酸運輸?shù)鞍妆磉_水平的影響[D];安徽醫(yī)科大學;2015年

7 魏璇;PPARγ通過對RUVBL2表達調(diào)控影響脂聯(lián)素分泌的研究[D];華中農(nóng)業(yè)大學;2015年

8 游潔冰;PPARγ激動劑、胰島素通過上調(diào)負性炎性因子TIPE2的表達抑制高糖、Aβ1-40引起的炎性反應(yīng)及神經(jīng)細胞調(diào)亡[D];山東大學;2015年

9 劉常為;CTGF、COL-I、PPARγ在卵巢細胞外基質(zhì)的表達及與多囊卵巢綜合征的關(guān)系[D];暨南大學;2015年

10 曹小潔;TLR4通過PPARγ下調(diào)ABCG1表達促進血管平滑肌細胞內(nèi)炎癥反應(yīng)及脂質(zhì)沉積[D];第三軍醫(yī)大學;2015年

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