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吉瑪慢病毒再次助力我國(guó)優(yōu)秀科學(xué)家登頂國(guó)際頂級(jí)期刊《CELL》
2020年9月14日，中山大學(xué)孫逸仙紀(jì)念醫(yī)院 蘇士成博士、許小丁博士及中山大學(xué)附屬第三醫(yī)院 高志良教授作為共同通訊作者，在國(guó)際頂尖學(xué)術(shù)期刊? Cell 在線發(fā)表題為：Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output 的研究論文。該研究確定了一種 線粒體特異性circRNA——SCAR，在 非酒精性脂肪性肝炎（NASH）中表達(dá)下調(diào)，向線粒體特異性遞送SCAR，可降低線粒體活性氧 （mROS）輸出，減輕炎癥，可作為NASH的治療靶標(biāo)。
非酒精性脂肪性肝炎（NASH）是 非酒精性脂肪性肝病（NAFLD）的炎癥亞型，伴有肝脂肪變性以及肝細(xì)胞損傷和炎癥的證據(jù)，伴或不伴肝纖維化。隨著時(shí)間的推移， NASH可能進(jìn)展為肝硬化、終末期肝病或需要肝移植。非酒精性脂肪性肝炎患者的肝病致殘率和病死率顯著高于單純性脂肪肝。
線粒體（mitochondrion），是細(xì)胞的“ 能量工廠”，線粒體發(fā)揮重要的細(xì)胞功能，通過(guò)氧化磷酸化 （OXPHOS）調(diào)節(jié)能量供應(yīng)，執(zhí)行細(xì)胞死亡以及Ca離子和活性氧（ROS）的細(xì)胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)，線粒體 在免疫代謝疾病中也起到了關(guān)鍵作用。
研究團(tuán)隊(duì)通過(guò)對(duì)非酒精性脂肪性肝炎（NASH）患者肝成纖維細(xì)胞的circRNA表達(dá)譜分析，發(fā)現(xiàn)線粒體circRNA占NASH成纖維細(xì)胞下調(diào)circRNA的相當(dāng)一部分。觀察到位于線粒體中的 circRNA——SCAR，抑制線粒體活性氧 （mROS）輸出和成纖維細(xì)胞活化。由PGC-1α介導(dǎo)的circRNA SCAR與ATP5B結(jié)合，并通過(guò)構(gòu)建慢病毒shRNA干擾阻斷CypD-mPTP相互作用而關(guān)閉 線粒體通透轉(zhuǎn)運(yùn)孔道（mPTP）。脂質(zhì)超載通過(guò)內(nèi)質(zhì)網(wǎng)應(yīng)激誘導(dǎo)的 C/EBP-同源蛋白（CHOP）抑制PGC-1α。動(dòng)物體內(nèi)實(shí)驗(yàn)也表明，靶向circRNA SCAR可減輕高脂飲食引起的肝硬化和胰島素抵抗。而在臨床上，circRNA SCAR與脂肪變性到NASH的進(jìn)展有關(guān)。
通過(guò)該研究，我國(guó)科學(xué)家又進(jìn)步確定了一種線粒體中的新型circRNA——SCAR，可作為非酒精性脂肪性肝炎（NASH）的治療靶標(biāo)，為我們今后攻克該疾病提供了新的研究方向。
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Figure 5. circRNA SCAR Shuts Down mPTP by Preventing CypD-mPTP Interaction
(A) Normal fibroblasts were treated with palmitate in the presence of mito-NP containing empty vectors (Vector), wild-type (SCAR), or mutated (SCAR-mut) circRNA SCAR overexpression vectors. Their mPTP opening was measured by calcein loading/CoCl2 quenching (n = 4 patients).
(B) In vitro RNA/protein interaction assay between recombinant ATP5B and indicated biotin-labeled circRNAs (n = 3).
(C) Normal fibroblasts were treated with palmitate in the presence of mito-NP containing wild-type or mutated circRNA SCAR overexpression vectors. Representative western blots of CypD and ATP5B (subunit of ATP synthase) in the ATP synthase-immunoprecipitated lysates are shown (n = 3 patients).
(D–G) Normal fibroblasts were treated with palmitate in the presence of mito-NP containing wild-type or mutated circRNA SCAR overexpression vectors. In some experiments, fibroblasts were pre-transduced with CypD-shRNAs.
(D) mPTP opening (upper) and ΔΨm (lower) were measured by calcein loading/CoCl2 quenching and JC-1 staining, respectively (n = 3 patients).
(E) Cytosolic ROS levels were detected by cytoORP via confocal microscopy. The 405/488 nm excitation ratio was quantitated (n = 5 patients).
(F) Fibroblast contractility in collagen matrices (n = 3 patients).
(G) Indicated cytokines were examined by ELISA (n = 4 patients).
注：材料方法中shRNA and siRNA Mediated Silencing
For shRNA transduction, a lentiviral vector plasmid pLKO.1-puro (GenePharma Inc, Shanghai, China) was used to construct the stable clones.?
吉瑪基因病毒產(chǎn)品近幾年已經(jīng)連續(xù)多次助力我國(guó)科學(xué)家在頂級(jí)期刊CNS上發(fā)表重要科學(xué)論文（參見(jiàn)相關(guān)鏈接https://mp.weixin.qq.com/s/PdkI8YelrpYLRupy-lFz9Q）。近期我們又推出了新的產(chǎn)品方案和促銷方案，歡迎大家積極關(guān)注索取相關(guān)產(chǎn)品和服務(wù)信息。吉瑪基因是您攀登科學(xué)高峰的永久忠實(shí)伙伴。
參考文獻(xiàn)
1. Zhao et al., Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output, Cell (2020), https://doi.org/10.1016/j.cell.2020.08.009
2. C.Y. Yu et al.,The circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency. Nat. Commun., 8 (2017), p. 1149