本文選題：8DSS + 毛乳頭細(xì)胞��； 參考：《第三軍醫(yī)大學(xué)》2015年博士論文

【摘要】：研究背景毛發(fā)具有防御、保護(hù)及增加信息交流和美觀的作用。毛發(fā)由毛囊生成,毛囊是一種結(jié)構(gòu)復(fù)雜的皮膚附屬器官,持續(xù)經(jīng)歷著生長(zhǎng)期、退行期和休止期的周期循環(huán)性生長(zhǎng)。毛囊周期一旦失調(diào),將會(huì)影響毛囊正常生長(zhǎng)從而導(dǎo)致脫發(fā)疾病的發(fā)生。隨著社會(huì)發(fā)展,人們對(duì)具有保護(hù)與美觀作用的毛發(fā)越來越重視,但臨床上療效確切的促毛發(fā)生長(zhǎng)藥物仍十分匱乏。目前,僅美國(guó)FDA批準(zhǔn)的口服藥物非那雄胺和外用藥物米諾地爾具有較肯定的療效。因此,對(duì)促進(jìn)毛囊再生、毛發(fā)生長(zhǎng)藥物的研究逐漸成為皮膚學(xué)領(lǐng)域的研究熱點(diǎn)與難點(diǎn)。毛乳頭(DP)是毛囊的主要間充質(zhì)成分,毛乳頭細(xì)胞是構(gòu)成毛乳頭的主要間質(zhì)細(xì)胞,具有維持誘導(dǎo)上皮細(xì)胞增殖分化形成毛囊,促進(jìn)毛發(fā)生長(zhǎng)發(fā)育和調(diào)控毛囊周期循環(huán)的能力。鑒于毛乳頭細(xì)胞具有誘導(dǎo)非毛發(fā)皮膚毛囊形成的能力,毛乳頭細(xì)胞可以作為應(yīng)于脫發(fā)疾病的治療的靶細(xì)胞。毛乳頭細(xì)胞能分泌多種細(xì)胞因子如干細(xì)胞生長(zhǎng)因子(SCF)、血管內(nèi)皮細(xì)胞生長(zhǎng)因子(VEGF)、肝細(xì)胞生長(zhǎng)因子(HGF)、胰島素樣生長(zhǎng)因子(IGF)、轉(zhuǎn)化生長(zhǎng)因子β(TGF-β)、骨形成蛋白(BMP)等生長(zhǎng)因子和信號(hào)轉(zhuǎn)導(dǎo)分子刺激上皮細(xì)胞增殖、分化,啟動(dòng)毛囊進(jìn)入生長(zhǎng)期,促進(jìn)毛囊的生長(zhǎng)發(fā)育。啟動(dòng)休止期毛囊激活的機(jī)制仍不清楚,但是認(rèn)為來源于毛乳頭的信號(hào)發(fā)揮了至關(guān)重要的作用,阻斷毛乳頭細(xì)胞與Wnt信號(hào)通路應(yīng)答的能力將使毛乳頭細(xì)胞分泌誘導(dǎo)上皮細(xì)胞增殖分化的細(xì)胞因子的能力下降,導(dǎo)致毛囊周期失調(diào)。在調(diào)控毛乳頭細(xì)胞相關(guān)的復(fù)雜信號(hào)通路網(wǎng)絡(luò)研究中,細(xì)胞信號(hào)傳導(dǎo)(cell signal transduction)日益受到人們重視。經(jīng)典信號(hào)通路Wnt/β-catenin信號(hào)對(duì)于毛乳頭細(xì)胞的增殖、細(xì)胞因子分泌及誘導(dǎo)毛囊再生至關(guān)重要,是調(diào)控毛囊發(fā)育必須的、最早期和最重要的信號(hào)之一。糖原合成激酶3β(GSK-3β)為Wnt/β-catenin經(jīng)典信號(hào)通路的關(guān)鍵分子,GSK-3β激酶失活可激活Wnt/β-catenin信號(hào)通路,維持毛乳頭細(xì)胞誘導(dǎo)上皮細(xì)胞增殖、分化及調(diào)節(jié)細(xì)胞周期的能力,從而促進(jìn)毛囊生長(zhǎng)發(fā)育。GSK-3β不僅是β-catenin通路激活的關(guān)鍵分子,同時(shí)也是PI3K/Akt信號(hào)通路重要的下游靶基因,激活PI3K/Akt通路,磷酸化gsk-3β,從而抑制gsk-3β活性可促進(jìn)細(xì)胞增殖,阻礙細(xì)胞的凋亡。天冬氨酸-絲氨酸-絲氨酸(dss)是牙本質(zhì)磷蛋白(dpp)中一個(gè)氨基酸重復(fù)序列。8dss是一種人工合成的由8個(gè)dss重復(fù)序列組成的多肽。8dss有很強(qiáng)的結(jié)合鈣離子的能力,并在牙齒基質(zhì)的沉積以及礦化過程起到重要作用。研究發(fā)現(xiàn)8dss外用于balb/c小鼠脫毛區(qū)域后可促進(jìn)該部位毛發(fā)再生(pub.no.us2010/0239503a1)。據(jù)此我們推測(cè)8dss極可能通過對(duì)pi3k/akt/gsk-3β通路的影響從而調(diào)控毛囊生長(zhǎng)周期進(jìn)而實(shí)現(xiàn)對(duì)毛發(fā)生長(zhǎng)的促進(jìn)作用。為了驗(yàn)證這一猜想,我們以毛囊生長(zhǎng)周期為切入點(diǎn),圍繞wnt/β-catenin和pi3k/akt信號(hào)通路,采用real-timepcr,westernblot等方法從細(xì)胞及分子水平探討了8dss對(duì)毛乳頭細(xì)胞誘導(dǎo)功能及wnt/β-catenin和pi3k/akt信號(hào)通路的影響及其作用機(jī)制,并在脫發(fā)小鼠模型上進(jìn)行了功能驗(yàn)證,以期揭示8dss在毛發(fā)生長(zhǎng)中的作用及其作用機(jī)制。本研究將可能為脫發(fā)性疾病提供新的治療靶點(diǎn)和防治策略。目的1、驗(yàn)證8dss能否促進(jìn)c57bl/6脫毛小鼠毛發(fā)生長(zhǎng)及其對(duì)毛囊生長(zhǎng)周期的影響2、探討8dss是否具有調(diào)控毛乳頭細(xì)胞增殖、分泌細(xì)胞因子、信號(hào)分子的作用;3、探討8dss是否通過調(diào)控pi3k/akt/gsk-3β信號(hào)通路參與調(diào)控毛乳頭細(xì)胞分泌功能從而促進(jìn)毛囊的生長(zhǎng)發(fā)育。材料與方法1、將熒光1%8dss涂抹于處于生長(zhǎng)期小鼠背部脫毛區(qū)域,觀察8dss滲透途徑。在小鼠脫毛區(qū)域涂抹1%8dss后,于不同時(shí)間點(diǎn)觀察鼠背皮膚顏色變化及毛發(fā)生長(zhǎng)情況;取用藥7天后小鼠背部皮膚,利用he染色觀察鏡下毛囊形態(tài)變化情況;利用免疫組化檢測(cè)毛囊中β-catenin表達(dá)情況;2、采用“二步酶消化法”提取毛乳頭,進(jìn)行毛乳頭細(xì)胞培養(yǎng);利用免疫熒光鑒定毛乳頭細(xì)胞。3、利用cck8法檢測(cè)8dss對(duì)毛乳頭細(xì)胞增殖的影響;利用rt-pcr檢測(cè)8dss對(duì)毛乳頭細(xì)胞分泌細(xì)胞因子、信號(hào)分子的影響;4、利用westernblot檢測(cè)p-gsk-3β及p-akt、bcl-2及核內(nèi)β-catenin表達(dá)水平。5、利用特異性抑制劑ly294002阻斷pi3k/akt信號(hào)通路后,利用westernblot檢測(cè)p-gsk-3β及p-akt水平的表達(dá)。結(jié)果1、8dss能夠沿毛囊皮脂腺途徑滲透熒光8dss局部涂抹脫毛部位皮膚后1小時(shí)觀察到綠色熒光主要分布在表皮,2小時(shí)后8dss逐漸沿毛囊外毛根鞘部位滲透到達(dá)整個(gè)毛囊,說明8dss能夠作用于毛囊部位。2、8dss能夠誘導(dǎo)毛囊周期性再生8dss溶液局部涂抹于小鼠脫毛部位后,觀察到小鼠背部皮膚顏色粉紅色到黑色的轉(zhuǎn)變時(shí)間早于陰性對(duì)照組,說明8dss能夠使毛囊從休止期提前進(jìn)入生長(zhǎng)期,從而促進(jìn)毛發(fā)生長(zhǎng)。he染色后顯微鏡下見8dss處理組毛囊生長(zhǎng)期呈iv期表現(xiàn)變,而陰性對(duì)照組呈ii期表現(xiàn)。免疫組化顯示8dss處理組毛囊顯著表達(dá)β-catenin。3、8dss能夠誘導(dǎo)毛乳頭細(xì)胞分泌信號(hào)分子cck8檢測(cè)結(jié)果顯示8dss在不能促進(jìn)毛乳頭細(xì)胞增殖,低濃度8dss對(duì)毛乳頭細(xì)胞增殖無明顯影響,隨著濃度升高對(duì)毛乳頭細(xì)胞反有抑制作用;但是通過rt-pcr分析發(fā)現(xiàn),低濃度8dss處理的毛乳頭細(xì)胞內(nèi)wnt信號(hào)通路相關(guān)基因和轉(zhuǎn)錄因子如wnt10b,lef-1和c-myc的表達(dá)上調(diào),提示8dss雖不能促進(jìn)毛乳頭細(xì)胞增殖,但能促進(jìn)毛乳頭細(xì)胞的誘導(dǎo)上皮細(xì)胞增殖、分化的能力。4、8dss可誘導(dǎo)核內(nèi)β-catenin蛋白激活wnt/β-catenin信號(hào)8dss處理毛乳頭細(xì)胞后1h、24h后用westernblot檢測(cè)結(jié)果顯示核內(nèi)β-catenin蛋白表達(dá)逐漸增強(qiáng),并呈時(shí)間依賴性,提示8dss可顯著增加wnt/β-catenin信號(hào)通路在毛乳頭細(xì)胞內(nèi)的活性,激活wnt/β-catenin信號(hào)通路。5、8dss能激活毛乳頭細(xì)胞內(nèi)pi3k/akt信號(hào)通路8dss處理后5min、15min、30min、60min用westernblot檢測(cè)結(jié)果顯示:抗凋亡因子bcl-2、p-gsk-3β及p-akt表達(dá)顯著增強(qiáng)并呈時(shí)間依賴性,提示8dss可激活毛乳頭細(xì)胞內(nèi)pi3k/akt信號(hào)通路,并促進(jìn)其下游靶基因bcl-2的表達(dá)抗細(xì)胞凋亡,使gsk-3β蛋白磷酸化而失活。6、8dss經(jīng)由pi3k/akt/gsk-3β信號(hào)發(fā)揮誘導(dǎo)毛囊周期性再生作用ly294002阻斷pi3k/akt信號(hào)通路后8dss不能增強(qiáng)gsk-3β及akt磷酸化水平,提示8dss增加wnt/β-catenin信號(hào)通路在毛乳頭細(xì)胞內(nèi)的活性可能是通過激活pi3k/akt/gsk-3β信號(hào)通路實(shí)現(xiàn)。結(jié)論1、8dss能調(diào)控毛囊周期性再生,具有促進(jìn)毛發(fā)生長(zhǎng)的作用。這為臨床提供新的脫發(fā)疾病治療藥物提供了有意義的實(shí)驗(yàn)資料。2、8dss能夠促進(jìn)毛乳頭細(xì)胞分泌wnt相關(guān)基因及增強(qiáng)核內(nèi)β-catenin蛋白表達(dá),PI3K/Akt/GSK-3β信號(hào)通路是8DSS調(diào)控毛乳頭細(xì)胞這種功能的關(guān)鍵信號(hào)通路,這為8DSS以后用于臨床上治療脫發(fā)疾病提供了重要的理論參考。
[Abstract]:Background hair has the function of defending, protecting and increasing information exchange and beauty. Hair is produced by hair follicle. Hair follicle is a complex structure of skin accessory, which continues to undergo cycle cycle growth during the period of growth, degenerative period and rest period. Once the hair follicle cycle is in disorder, it will affect the normal growth of the hair follicle and lead to hair loss. With the development of society, people pay more and more attention to the hair which has the role of protection and beauty, but the clinically effective medicine for promoting hair growth is still very scarce. At present, only the American FDA approved oral drug, finasteride and external drug minoxidil, has a more positive effect. Therefore, it is necessary to promote hair follicle regeneration and hair growth. The study of drugs has gradually become a hot and difficult point in the field of dermatology. DP is the main interstitial component of hair follicles. The dermal papilla cells are the main interstitial cells of hair nipples, which have the ability to maintain the proliferation and differentiation of epithelial cells to form hair follicles, promote the growth and development of hair and regulate the cycle cycle of hair follicles. The head cells have the ability to induce the formation of non hairy skin follicles, and dermal papilla cells can be used as target cells for the treatment of hair loss. The dermal papilla cells can secrete a variety of cytokines such as stem cell growth factor (SCF), vascular endothelial growth factor (VEGF), liver cell growth factor (HGF), and insulin like growth factor (IGF). Growth factor beta (TGF- beta), bone morphogenetic protein (BMP) and other growth factors and signal transduction molecules stimulate epithelial cell proliferation, differentiation, initiation of hair follicles entering the growth period, promoting the growth and development of hair follicles. The mechanism of activating the hair follicle at the end of the rest period is still unclear, but it is considered that the signal from the hair nipple has played a vital role in blocking the hair milk. The ability of the head cells to respond to the Wnt signaling pathway will decrease the ability of the dermal papilla cells to induce the proliferation and differentiation of epithelial cells and lead to the dysregulation of hair follicles. In the study of the complex signaling pathway related to the regulation of dermal papilla cells, cell signal transduction is becoming more and more important. The signal pathway Wnt/ beta -catenin signal is very important for the proliferation of dermal papilla cells, cytokine secretion and induction of hair follicle regeneration. It is one of the most important signals to regulate the development of hair follicles. The glycogen kinase 3 beta (GSK-3 beta) is the key molecule of the classical signaling pathway of Wnt/ beta -catenin, and the inactivation of GSK-3 beta kinase activates Wnt/ beta. Catenin signaling pathway, which maintains the ability of dermal papilla cells to induce epithelial cell proliferation, differentiation and regulation of cell cycle, thus promotes the growth and development of.GSK-3 beta not only a key molecule in the activation of the beta -catenin pathway, but also an important downstream target gene of the PI3K/Akt signaling pathway, activating the PI3K/Akt pathway, phosphorylating GSK-3 beta, and thus inhibiting the gsk- 3 beta activity can promote cell proliferation and inhibit cell apoptosis. Aspartic acid serine serine (DSS) is an amino acid repeat sequence.8dss in dentin phosphate (DPP), a synthetic polypeptide composed of 8 DSS repeats, which has a strong ability to bind calcium ions, and in the deposition and mineralization of dental matrix. The study found that 8dss was used to promote hair regeneration (pub.no.us2010/0239503a1) in the balb/c mice after being used in hair removal (pub.no.us2010/0239503a1). Therefore, we speculate that the 8dss may regulate the growth cycle of the hair follicle by regulating the growth cycle of the follicle to promote the growth of hair. In order to verify this guess, With the growth cycle of hair follicles as a breakthrough point, we studied the effects and mechanism of 8dss on the induction of dermal papilla cells and the wnt/ beta -catenin and pi3k/akt signaling pathways from the cellular and molecular levels around wnt/ beta -catenin and pi3k/akt signaling pathways, using real-timepcr, Westernblot and other methods, and the function of 8dss in the hair loss mouse model was carried out. The purpose of this study is to reveal the role of 8dss in hair growth and its mechanism of action. This study may provide new therapeutic targets and prevention strategies for hair loss. 1, the purpose of this study is to verify whether 8dss can promote hair growth and the growth cycle of hair follicles in c57bl/6 hairy mice, and to explore whether 8dss can regulate the proliferation of dermal papilla cells. The role of secreting cell factors and signal molecules; 3, to explore whether 8dss promotes the growth and development of hair follicles by regulating the pi3k/akt/gsk-3 beta signaling pathway to regulate the secretory function of dermal papilla cells. Materials and methods 1, smear fluorescent 1%8dss on the back depilatory region of the growth stage of mice and observe the 8dss infiltration pathway. After applying 1%8dss, the skin color changes and hair growth were observed at different time points. After taking medication for 7 days, the morphological changes of the hair follicles were observed by HE staining, and the expression of beta -catenin in the hair follicles was detected by immunohistochemistry; 2, the papilla cell culture was extracted by the "two step enzyme digestion", and the dermal papilla cells were cultured. .3 was used to detect the effect of 8dss on the proliferation of dermal papilla cells by CCK8, and the effect of 8dss on the secretion of cytokines and signal molecules by 8dss in dermal papilla cells. 4, Westernblot was used to detect p-gsk-3 beta and p-Akt, Bcl-2 and the expression level of beta -catenin was.5, and specific inhibitor LY294002 was used. After blocking the pi3k/akt signaling pathway, Westernblot was used to detect the expression of p-gsk-3 beta and p-Akt. Results 1,8dss was able to observe the green fluorescence in the epidermis for 1 hours along the sebaceous gland pathway of the hair follicle, and observed that the green fluorescence was mainly in the epidermis. After 2 hours, 8dss gradually penetrated into the whole hair follicle along the outer hair root sheath of the hair follicle. It is indicated that 8dss can act on the hair follicle site.2,8dss to induce the periodic regeneration of the hair follicle by applying the 8dss solution to the depilatory part of the mouse. The time of the color pink to black change of the mouse's back skin is earlier than that of the negative control group. It shows that the 8dss can advance the hair follicle from the rest period to the growth period, thus promoting the growth of hair.He. The growth period of the follicle in the 8dss treatment group was IV stage after staining, and the negative control group showed II stage performance. The immunohistochemical staining showed that the expression of beta -catenin.3,8dss in the hair follicle in the 8dss treatment group could induce the CCK8 detection of the secretory signal molecules of the dermal papilla cells, which showed that 8dss could not promote the proliferation of dermal papilla cells and the low concentration 8dss to hair milk. The proliferation of head cells had no obvious effect on the proliferation of dermal papilla cells. However, RT-PCR analysis showed that the expression of Wnt signaling pathway related genes and transcription factors such as Wnt10b, LEF-1 and c-myc in the dermal papilla cells treated with low concentration of 8dss increased, suggesting that 8dss could not promote the proliferation of dermal papilla cells, but could promote the proliferation of dermal papilla cells. The proliferation of epithelial cells induced by the dermal papilla cells, the ability of.4,8dss to induce beta -catenin protein to activate wnt/ beta -catenin signal 8dss to treat 1h in dermal papilla cells after 24h, and Westernblot detection results showed that the expression of beta -catenin protein in the nucleus increased gradually after 24h, and was dependent on the time dependence, suggesting that 8dss can significantly increase wnt/ beta -catenin signal. The activity of the pathway in the dermal papilla cells, activating the wnt/ beta -catenin signaling pathway.5,8dss can activate the pi3k/akt signaling pathway in the dermal papilla cells after 8dss treatment, 5min, 15min, 30min, and 60min using Westernblot detection results show that the anti apoptotic factor Bcl-2, p-gsk-3 beta and expression are significantly enhanced and time dependent, suggesting that the dermal papilla can be activated. The intracellular pi3k/akt signaling pathway and promoting the expression of the downstream target gene Bcl-2 against apoptosis, the GSK-3 beta protein phosphorylation and inactivation of.6,8dss via pi3k/akt/gsk-3 beta signal to induce the periodic regeneration of the hair follicle by LY294002 blocking the pi3k/akt signaling pathway, 8dss can not enhance the GSK-3 beta and Akt phosphorylation level, suggesting 8dss increase of wnt/ beta. The activity of -catenin signaling pathway in the dermal papilla cells may be realized by activating the pi3k/akt/gsk-3 beta signaling pathway. Conclusion 1,8dss can regulate the periodic regeneration of hair follicles and promote hair growth. This provides a meaningful experimental data for the clinical treatment of new hair loss diseases,.2,8dss can promote dermal papilla cells. Secreting Wnt related genes and enhancing the expression of beta -catenin protein in the nucleus, PI3K/Akt/GSK-3 beta signaling pathway is the key signal pathway for the function of 8DSS to regulate the function of dermal papilla cells, which provides an important theoretical reference for the clinical treatment of hair loss after 8DSS.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R339.1

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