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mTOR 在眼科疾病中的研究进展

Progress on mTOR in eye diseases

来源期刊： 眼科学报 | 2024年1月 第39卷 第1期： 27-36 发布时间：2024-01-28 收稿时间：2024/3/22 9:04:56 阅读量：1543
作者：
华耘,
赵新荣,
关键词：
哺乳动物雷帕霉素靶蛋白翼状胬肉年龄相关性黄斑变性青光眼角膜新生血管
mTOR pterygium age-related macular degeneration glaucoma corneal neovascularization
DOI：
10.12419/2312260005
哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是一种蛋白激酶，在体内主要参与营养水平、生长代谢的调节。mTOR是癌症、衰老和其他代谢相关病理性疾病的重要靶点，参与了增殖、转分化、自噬等多种生物学过程。眼被认为是具有免疫特权的区域，由于血管系统会影响视力，眼的血管系统位于中心光路以外。眼的许多区域都有将免疫细胞运输至发育不良、受损或衰老有关的病变部位的机制。尽管免疫应答主要是为了修复或保护自身，但是免疫细胞可能会分泌一些细胞因子，导致炎症或纤维化，进而损害视力。研究证实，mTOR与翼状胬肉、年龄相关性黄斑变性(age-related macular degeneration,AMD)、青光眼、白内障、糖尿病视网膜病变(diabetic retinopathy,DR)、眼部肿瘤等多种眼病密切相关。目前，mTOR抑制剂通常被用作免疫抑制剂，用于癌症的治疗，但mTOR抑制剂用于眼部疾病的报道尚少。因此，该文就mTOR信号通路在相关眼科疾病中的作用、调控机制、药物治疗等方面进行简要综述，为相关眼科疾病的病理机制与治疗提供思路，以便后续开展更深入的研究。
Mammalian target protein of rapamycin (mTOR) is a protein kinase that primarily involves in the regulation of nutrient levels andgrowth metabolism in vivo. mTOR serves as a crucial target for cancer, aging, and other metabolic related pathological diseases, participating in various biological processes such as proliferation, transdifferentiation, and autophagy. Te eye is considered an area with immune privilege, as the vascular system afects vision and is located outside the central light path. Many areas of the eye have mechanisms for transporting immune cells to the afected areas related to developmental, damaged, or aging. Although the immune response is primarily aimed at reparing or protecting itself, immune cells may secrete some cytokines, leading to infammation or fbrosis, which in turn can damage vision. Results from studies have confirmed that mTOR is closely related to pterygium, age-related macular degeneration (AMD), glaucoma, cataract, diabetic retinopathy (DR), eye tumors and other eye diseases. Currently, mTOR inhibitors are widely used as immunosuppressants and approved for cancer treatment; however, there are few reports on the use of mTOR inhibitors for eye diseases. Therefore, in the article it provides a brief overview of the role, regulatory mechanisms, and drug treatment of the mTOR signaling pathway in related ophthalmic diseases, providing ideas for the pathological mechanisms and treatment of related ophthalmic diseases, in order to carry out more in-depth research in the future.
哺乳动物雷帕霉素靶蛋白(mammaliantarget of rapamycin,mTOR)信号通路是一个重要的真核生物信号通路，该信号通路协调细胞生长与环境条件，并在细胞和生物体生理中起着重要作用[1]。在正常细胞中，mTOR受到来自氨基酸、生长因子、应激、氧化还原传感器和能量的各种刺激。接受刺激后，活跃的mTOR促进细胞合成代谢，产生各种大分子，如核酸、蛋白质、脂质，这些大分子参与细胞生物量、核糖体生物发生和蛋白质翻译。mTOR还阻断分解代谢过程，是细胞代谢的主要调节因子。mTOR通过整合这些刺激因素诱导的合成代谢过程，调节细胞的增殖与代谢途径。此外，mTOR在自噬的调控中也起着核心作用[2]。mTOR介导的信号传导通路、mTOR的靶向治疗与耐药机制、mTOR在精准医学中的作用已取得一定的研究进展[2-3]。现有研究表明mTOR在肿瘤中过表达，且参与了视网膜下纤维化、视网膜母细胞瘤、乳腺癌、胃癌等疾病的增殖、侵袭、纤维化等过程[4-7]。mTOR在细胞增殖、自噬、代谢和免疫等多种生物过程中发挥着关键作用，mTOR活性失调与多种疾病的病理生理状况改变有关，如衰老、阿尔茨海默病、糖尿病、肥胖和癌症等[3, 8]。mTOR作为一个癌症治疗的潜在靶点，目前在一些眼部疾病中也有研究，它可能与多种眼部疾病的发生、发展密切相关[9-10]。

1 mTOR的结构与功能

mTOR蛋白参与构成两种复合物，mTOR复合体1(mechanistic target of rapamycin complex 1,mTORC1)和mTOR复合体2(mTORC2)。mTORC1对雷帕霉素敏感，mTORC2不受雷帕霉素的直接抑制[11]。对雷帕霉素敏感的mTORC1由mTOR调节相关蛋白(regulatory associated protein of mTOR ,raptor)和哺乳动物致死蛋白SEC-13蛋白8(mammalian lethal with SEC13 protein 8,mLST8)与mTOR结合形成，而对雷帕霉素不敏感的mTORC2由mTOR复合物的RPTOR独立伴侣2(raptor independent companion of mTOR complex 2,rictor)、应激活化蛋白激酶作用蛋白1(sapk interacting protein1,SIN1)和mLST8结合mTOR形成[11-12]。含有鼠蓬乱蛋白、产卵缺陷10蛋白、血小板-白细胞C激酶底物2蛋白(dishevelled,egl-10 and pleckstrin,DEP)结构域的mTOR相互作用蛋白(DEP domain-containing mTOR-interacting protein,DEPTOR)是mTORC1和mTORC2的调控成分。DEPTOR可能通过PDZ结构域(psd95-discs large-zo1)与mTOR结合而抑制mTORC1与mTORC2[13]。mTORC1和mTORC2的最佳活性是维持代谢与健康以及预防疾病的重要条件。mTORC1的激活受氨基酸、葡萄糖、脂类等营养物质或代谢产物的调节。在营养限制或其他环境压力的存在下，mTORC1受到不同机制的调控。如在减少生长因子/磷脂酰肌醇-3-激酶(phosphatidylinositol 3kinase,PI3K)信号的过程中，TSC1/TSC2复合体起到负向调节mTORC1的作用；在生长因子存在的情况下，富含脯氨酸蛋白激酶B底物蛋白(prolin-rich protein kinase B substrate protein,PRAS40)被Akt和mTOR磷酸化，并从mTORC1上解离，从而解除对mTORC1的抑制。与mTORC1相比，mTORC2的调控过程似乎更复杂[11, 13]。mTORC1调节细胞生长和代谢，而mTORC2主要通过磷酸化蛋白激酶A/蛋白激酶G/蛋白激酶C(protein kinase A/protein kinase G/protein kinase C,AGC)蛋白激酶家族的几个成员来控制细胞的增殖和存活[1]。生长因子以及其他营养物质、代谢水平波动、其他应激条件等都能影响mTORC2的激活。mTORC2还能与其他Ras相关蛋白包括Rac1、Rho、Rap1、Rit和Ryh1的相互作用，调节mTORC2的活性。来自mTORC1的反馈信号也可以调节mTORC2的激活[11]。此外，mTORC2还能在活性氧(reactive oxygen species,ROS)的诱导下激活，进而参与慢性自噬过程，而mTORC2激活反过来又在不同的细胞亚群中促进衰老激活和肌成纤维细胞分化[14]。

2 mTOR与翼状胬肉

翼状胬肉(pterygium)是一种常见的慢性增殖性疾病，具有类似肿瘤样特性，导致翼状胬肉形成的主要环境因素是紫外线辐射，此外还有细胞增殖、抗细胞凋亡、氧化应激、炎症介质以及免疫调控等机制。上皮细胞增殖、纤维血管生长、慢性炎症以及显著的细胞外基质重塑等被认为是该疾病的主要病理特征[15]。成纤维细胞在翼状胬肉的发病中起着重要的作用。α-肌动蛋白(α-smooth muscle actin,α-SMA)高表达于肌成纤维细胞，促进上皮细胞向间质转化。转化生长因子-β1(transforming growth factor-β1, TGF-β1)作为一种重要的纤维化诱导因子，可诱导其向上皮-间质转化。前期研究发现，在翼状胬肉组织中，TGF-β1和αSMA的表达明显升高，表明眼内成纤维细胞的纤维化在翼状胬肉发展过程中起重要作用[16]。既往研究已证实mTOR在人翼状胬肉成纤维细胞(human pterygium fibroblasts,HPFs)中过表达，且参与促进HPFs的增殖和转分化过程。当使用雷帕霉素特异性阻断mTOR时，HPFs的增殖、转分化受到抑制[17]。与正常人结膜标本相比，mTORC1在翼状胬肉中高度激活。mTORC1激活后可通过靶向B淋巴细胞瘤-2基因(members of the B cell lymphoma 2,Bcl-2)调节Beclin1依赖的自噬，抑制翼状胬肉的细胞凋亡。mTORC1还通过抑制p73对成纤维细胞生长因子受体3(fibroblast growth factor receptor3,FGFR3)进行负性调节，从而刺激HPFs的增殖[18]。mTORC2-Akt轴在TGF-β1诱导的HPFs向肌成纤维细胞分化的过程中也发挥了重要作用，当使用mTOR的活性位点抑制剂Torin2抑制HPFs中mTORC1和mTORC2活性时，TGF-β1诱导的α-SMA和重组人纤维连接蛋白片段(recombinant human fibronectin fragment, Fibronectin)的表达受到抑制[19]。一种新型长链非编码RNA(long non-coding RNA,lncRNA)，即翼状胬肉正相关的lncRNA(pterygium positively-related lncRNA,lnc-PPRL)被发现主要在翼状胬肉细胞的胞质中积累，lnc-PPRL可能通过激活经典的PI3K/丙酮酸脱氢酶激酶1(pyruvate dehydrogenase kinase 1,PDK1)通路，促进Akt/mTOR信号通路及其下游效应因子的激活而发挥其生物学效应，进而促进人翼状胬肉上皮细胞(human pterygium epithelial cells,hPECs)的增殖、迁移和侵袭[20]。Han等[21]研究发现，微RNA-218-5p(microRNA-218-5p,miR-218-5p)通过PI3K/Akt/mTOR信号通路靶向抑制表皮生长因子受体(epidermal growth factor receptor,EGFR)，进而抑制PECs的迁移和增殖。Liu等[22]研究发现，ZD6474通过抑制AKT-mTOR信号通路减弱HPFs的纤维化并抑制新生血管形成。上述研究成果以mTOR为干预靶点，对翼状胬肉的预防和治疗提供新的研究思路。但目前对于mTORC1与mTORC2在翼状胬肉中的研究还较为局限，且仅在细胞水平得到了初步研究，还需要进一步深入研究与此途径相关的调控靶点。由于翼状胬肉发病机制较为复杂,与环境、遗传、免疫等多方面因素有关，需要进一步增加紫外线干预等，才能诱发类翼状胬肉组织，目前国内外尚无成熟翼状胬肉动物模型的报道。仅有少数研究者通过切除颞上象限角膜缘干细胞(limbus stem cells,LSCs)+1.25%盐酸点眼刺激以建立兔眼翼状胬肉模型[23]，但此模型尚不成熟,有待进一步探究。

3 mTOR与年龄相关性黄斑变性

年龄相关性黄斑变性(age-related macular degeneration, AMD)是老年人视力损害的主要原因，视网膜色素上皮(retinal pigment epithelial,RPE)功能障碍和脉络膜新生血管(choroidal neovascularization,CNV)是AMD的主要特征，其发生机制尚不清楚[24]。目前，自噬在AMD发病机制中的关键作用逐渐显现，而mTOR是调控自噬的关键分子之一[25]。据报道，过度激活的mTORC1是AMD的RPE变性机制之一[26]。相对分子量为32 000的环状AMP调节磷酸化蛋白(cyclic amp-regulated phosphoprotein of molecular weight 32 000,DARPP-32)是一种新近发现的、受mTORC1调控的信号蛋白，可能与AMD的RPE变性有关[26]。Xie等[27]研究表明，核心蛋白聚糖(decorin,DCN)，一种小的富含亮氨酸的蛋白多糖，可以通过激活AMP活化蛋白激酶(amp-activated protein kinase,AMPK)/mTOR通路促进自噬，来保护RPE细胞免受H2O2诱导的氧化应激和凋亡，从而为AMD的预防和治疗提供了治疗潜力。Sun等[24]研究表明，AlkB同系物5 (AlkB homolog 5,ALKBH5)能通过磷脂酰肌醇-3激酶催化亚基2B (phosphatidylinositol-4-phosphate 3-kinase,catalytic subunit type 2 beta,PIK 3C 2B)介导的AKT/mTOR通路的激活而诱导AMD的RPE功能障碍和CNV进展。Wu等[28]研究表明，在AMD中，环状RNA-Uxs1(circRNA-Uxs1)通过与miR-335-5p结合，进一步上调胎盘生长因子(placental growth factor,PGF)基因的表达，激活mTOR/p70核糖体蛋白S6激酶(p70S6K)通路。由于视网膜下纤维化仍然是新生血管性年龄相关性黄斑变性(neovascular age-related macular degeneration,nAMD)的主要障碍。脉络膜周细胞被发现是视网膜下纤维化的一个重要来源。Zhao等[7]通过采用胶原α1-绿色荧光蛋白(collagen1α1-green fluorescent protein,Col1α1-GFP)报告基因的转基因小鼠激光诱导CNV形成，在体内外研究Akt/mTOR通路在周细胞-肌成纤维细胞转化(pericyte-myofibroblasttransition,PMT)导致的视网膜下纤维化中发现，转化生长因子-β2(transforming growth factor-β2, TGF-β2)通过Smad2/3和Akt/mTOR信号通路介导脉络膜周细胞增殖和PMT，阻断Akt/mTOR通路可减轻激光诱导CNV模型视网膜下纤维化。Ma等[29]在激光诱导的CNV小鼠模型中发现，与单独抑制血管内皮生长因子A(vascular endothelial growth factor A,VEGF-A)相比，阻断PI3K/mTOR通路可抑制激光诱导的脉络膜新生血管并改善预后，提示抑制PI3K/mTOR通路可能会阻断多种生长因子的作用而导致预后更好。Park等[30]在CNV小鼠模型中也证明了利用重组腺相关病毒(recombinant adeno-associated virus,rAAV)-mTOR短发夹RNA(short hairpin RNA,shRNA)抑制mTOR活性在治疗AMD相关CNV中的治疗潜力。这些研究结果表明，靶向mTOR调节可能是治疗AMD中RPE和CNV的一条潜在治疗途径。

4 mTOR与青光眼

青光眼是由视网膜神经节细胞(retinal ganglion cells, RGCs)丢失、视神经萎缩、视野缺损为特征的一种复杂的、多因素的神经退行性疾病，是导致不可逆性失明的最常见原因[31-32]。据报道，mTOR调控的自噬机制在青光眼的发生中起着重要作用[32]。雷帕霉素可通过抑制mTOR信号通路，在外周及中枢引起自噬。在视神经切断的动物模型中，雷帕霉素处理的小鼠在手术10 d后RGC的存活率提高了40%，显示出良好的效果[33]。Subramani等[34]在干细胞治疗青光眼退行性变的研究中发现，神经轴突导向因子1(Netrin-1)/结直肠癌缺陷基因(deleted in colorectal cancer,DCC)之间的相互作用可以促进轴突生长，还通过招募mTOR信号通路促进局部蛋白合成，进而促进RGCs轴突再生。这种情况说明，mTOR有助于成为干细胞治疗青光眼退行性变的潜在靶点。此外，在动物学实验中发现，雷帕霉素抑制mTOR后有效地阻止了青光眼的神经变性，支持了mTOR在扰乱新陈代谢和促进青光眼中的破坏性作用[35]。从机制上而言，雷帕霉素不仅抑制视网膜胶质细胞的活化，还降低焦亡诱导的炎症因子的表达水平。另外有学者认为，雷帕霉素对RGC轴突的保护作用，可能是通过抑制胶质细胞激活和调节mTOR/卷曲蛋白激酶(rho-associated coiled-coil containing protein kinase,ROCK)通路实现的[36]。这些发现揭示西罗莫司抗青光眼的新机制，为其在临床前研究中的应用提供进一步的依据。近年，中药方剂与中药有效成分在青光眼中的研究逐渐增多，袁安琪等[37]发现，川芎嗪有减低青光眼患者眼压、减轻临床症状的作用，其作用机制与PI3K/Akt/mTOR信号通路参与的自噬调节相关。川芎嗪还能减少高眼压模型大鼠RGCs的凋亡，其对视神经保护作用可能同样是基于对PI3K/Akt/mTOR信号通路靶向调控自噬来实现的。枸杞多糖也有干预自噬、减少RGCs凋亡作用，其机制可能与PI3K/Akt信号通路相关。杨稀瑞等[38]研究发现，通窍明目汤可通过介导p53/AMPK/mTOR信号通路上调RGC自噬水平，从而抑制青光眼视神经萎缩的进展。以上研究成果提示，mTOR可能成为治疗青光眼的潜在靶点。

5 mTOR与CNV

CNV是一种严重影响视力的眼科疾病致盲机制，常见于碱烧伤、外伤、角膜炎症、细菌、真菌及病毒感染等多种情况[39-41]。VEGF被认为是角膜创面愈合过程中的关键促血管生成因子。研究发现，外源性VEGF通过AKT/mTOR通路诱导CNV[42]。在碱烧伤的小鼠模型中发现，PI3K/AKT/mTOR信号通路参与了CNV。PI3K抑制剂，如雷帕霉素或wortmannin和LY294002，可明显降低角膜混浊和CNV的严重程度[40, 43-44]。姜黄素也被证明可通过抑制mTOR信号传导通路，降低VEGF蛋白的表达水平，从而抑制眼角膜碱烧伤后新生血管的生长[45]。Yang等[42]探讨miR-145/桩蛋白(paxillin,PXN)轴在VEGF-A诱导的角膜血管生成过程中细胞代谢的机制研究发现，miR-145-5p介导的PXN下调可通过PI3K/AKT/mTOR途径抑制线粒体能量代谢，从而缓解VEGF–A诱导的人脐静脉内皮细胞(human umbilicalvein endothelial cells,HUVECs)迁移和血管生成，PXN可能是抗血管生成治疗的潜在靶点。总之，mTOR在CNV中对VEGF的调控机制研究为靶向治疗CNV提供思路。

6 mTOR与白内障

晶状体发育过程中细胞增殖、分化和细胞器降解的缺陷可能导致先天性白内障。相反，成熟晶状体内环境平衡失调可能会导致年龄相关性白内障(age-related cataract,ARC)[46]。在糖尿病性白内障中，高葡萄糖水平也能通过mTOR信号通路抑制自噬[47]，这提示激活自噬或许能为糖尿病性白内障提供潜在治疗策略。在体外构建miR-124过表达的后发性白内障(posterior capsule opacification,PCO)模型中，miR-124调控晶状体上皮细胞增殖、迁移及凋亡可能与PI3K/AKT/mTOR信号通路有关[48]。通过研究转染mTOR-siRNA至人晶状体上皮细胞系B3(human lens epithelial line B3,HLE-B3)中，探究PI3K/AKT/mTOR信号通路蛋白p70S6K及真核细胞起始因子4E结合蛋白1(4E binding protein 1,4EBP1)的表达变化，并与雷帕霉素的作用对比，进一步说明mTOR在人晶状体上皮细胞的生长、增殖中的重要作用[49]。此外，Chen等[50]在ARC的研究中发现，二甲双胍可通过激活AMPK来恢复因氧化应激受损的自噬通量。二甲双胍还能通过改善溶酶体功能和失活mTOR来抑制人晶状体上皮细胞系B3(the human lens epithelial cell line,HLE-B3)细胞的衰老。这提示二甲双胍可能成为缓解ARC形成和发展的一个新的候选药物。在一项mTORC1与白内障的孟德尔随机化研究中也提出了mTORC1/真核翻译起始因子4E结合蛋白(eukaryotic translation initiation factor 4E binding protein,EIF4EBP)轴与白内障之间可能存在潜在的因果关系[51]，为更有效防治白内障的药理靶点提供依据。

7 mTOR与糖尿病视网膜病变

糖尿病性视网膜病变(diabetic retinopathy,DR)是一种视网膜微血管异常受损、退化和再生的疾病[52]。在DR过程中，mTOR通路参与多种合成代谢和分解代谢过程，如自噬、氧化应激、细胞死亡和促炎细胞因子的释放，进而参与协调视网膜神经退行性变[53-54]。在DR中，自噬的激活通过预防神经血管损伤起到保护作用[55]。ZOU等采用链脲佐菌素(streptozotocin,STZ)诱导糖尿病小鼠模型和高糖(high-glucose,HG)诱导RPE细胞系ARPE-19来建立DR的体内与体外模型，研究发现WIF1基因可以通过下调AMPK/mTOR通路改善ARPE-19细胞中DR引起的线粒体功能障碍，进而改善DR[56]。白细胞衍生趋化因子2(leukocyte cell-derived chemotaxin 2,LECT2)被证实可通过激活酪氨酸激酶受体2(tyrosine kinase receptors 2,Tie2)/Akt/mTOR信号通路，提高内皮间紧密连接蛋白水平，改善糖尿病继发性血管视网膜屏障损伤[57]。明目消蒙片(mingmu xiaomeng tablets,MMXM)被报道可能通过抑制PI3K/Akt/mTOR信号传导和增强自噬来保护糖尿病视网膜[58]。Li等[59]研究证实，在DR中，原花青素(procyanidin,PC)可能通过P53/mTOR自噬途径保护RPE细胞免受高糖损伤。Zhang等[60]研究发现，阿江榄仁酸(arjunolic acid,AA)可能是一种有希望的候选药物，通过AMPK/mTOR/血红素氧合酶１(hemeoxygenase1,HO-1)调节的自噬途径保护视网膜细胞免受STZ诱导产生的氧化应激和炎症反应。小檗碱也被证实可以通过Akt/mTOR/缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)/VEGF通路抑制胰岛素诱导的视网膜内皮细胞活化，改善胰岛素诱导的Ⅰ型和Ⅱ型DR[61]。Liu等[62]研究发现，Shabyar(SBA)是一种传统的中药，可以通过抑制醛糖还原酶和AMPK/mTOR/酶UNC-51样激酶-1(unc-51 like autophagy activating kinase1,ULK1)自噬通路来改善高糖诱导的RPE损伤。尽管有很多关于DR与mTOR相关的研究成果，但由于相关信号通路的复杂性，对其通路机制的深入和全面的研究仍然缺乏。从源头上治疗DR还需要更多基础研究，还需要更多的相关药物的临床评价。

8 mTOR与眼部肿瘤

mTOR是介导眼部肿瘤的关键因素之一，与肿瘤细胞的增殖，免疫细胞的募集有着一定的联系，如葡萄膜黑色素瘤(uvealmelanoma,UM)、视网膜母细胞瘤(retinoblastoma,RB)等。在UM中，肝素结合细胞因子(midkine)可以通过mTOR/核糖体蛋白S6(ribosomal protein S6,RPS6)促进UM的转移和治疗耐药[63]。此外，目前研究发现，适度浓度的碳点(Cdot)促进UM细胞的肿瘤发生，其致瘤作用主要是由于Cdot诱导ROS的产生，激活Akt/mTOR信号通路，增加谷氨酰胺代谢，从而促进UM细胞增殖和转移[64]。目前研究发现，miR-127-3p通过靶向下调丝裂原活化蛋白激酶4(mitogen activated protein kinase 4,MAPK4)来抑制UM细胞增殖、迁移和侵袭，诱导细胞凋亡，这可能与抑制AKT/mTOR通路激活有关[65]。miR-19对UM细胞增殖、凋亡、迁移和侵袭也有一定影响，敲低miR-19可抑制UM细胞增殖、迁移和侵袭能力并促进凋亡，其机制可能与EGFR/AKT/mTOR信号通路被抑制有关[66]。Farhan等[67]研究发现，青蒿素通过抑制PI3K/AKT/mTOR信号通路抑制UM的迁移和侵袭。在脉络膜黑色素瘤的研究中也发现，辣椒素可能通过调控AMPK/mTOR信号通路参与对C918和OCM-1细胞的增殖、迁移、自噬的调控[68]。在RB的研究中，miR-140-5p被证明能通过阻断细胞间充质上皮转化(cellular mesenchymal-epithelial transition,c-Met)/AKT/mTOR信号通路来抑制细胞生长[69]。木犀草素也被证明可抑制RB侵袭性和干样特性，这可能与抑制PI3K/AKT/mTOR信号通路有关[70]。杨娟等[71]通过构建体内外模型发现，蛇床子素可通过抑制PI3K/AKT/mTOR的活化来诱导RBY79细胞凋亡，并且对裸鼠体内的RB具有抑制作用。这些发现和报道揭示了mTOR信号通路在眼部肿瘤中的治疗潜能。

9 小结

目前，关于mTOR在眼病中的研究较为广泛，研究者主要基于细胞与动物实验结果指出mTOR信号通路是治疗各种眼科疾病有希望的靶点。常见的mTOR抑制剂如雷帕霉素已在临床中用于部分肿瘤的治疗[72]。其他的mTOR抑制剂如依维莫司[73]、Temsirolimus[74]、Sapanisertib[75]等目前还处于部分肿瘤的临床试验阶段，但特异性mTOR抑制剂在眼部疾病中的研究还较少。在一项探究mTOR抑制剂Palomid 529治疗nAMD的临床Ⅰ期试验中发现，连续结膜下注射Palomid 529，患者耐受性良好，未发现任何眼部或全身毒性[76]。现有的基础研究结果显示，雷帕霉素和其他mTOR抑制剂在促进角膜稳态方面显示出广泛的治疗效果，并且可能对翼状胬肉、圆锥角膜、角膜营养不良等疾病有益。但现有临床研究结果显示，雷帕霉素具有独特的免疫抑制机制，可能会引起一些不良反应，其抗纤维化功能在联合用药中可能获得更好的结果。在许多眼组织纤维化疾病中，PI3K/AKT信号通路位于mTORC1的上游和mTORC2的下游，在调节细胞存活、增殖和生长中起关键作用。从这个角度来看，PI3K/mTOR双特异性抑制剂同时使PI3K/AKT信号失活，可以解决生长信号刺激时对AKT的负反馈，并可能进一步防止眼组织局部伤口愈合过程中的新生血管形成或纤维化。综上所述，活化的mTOR在mTOR与翼状胬肉、AMD、青光眼、白内障、DR、眼部肿瘤等疾病的发病机制中占主导地位，雷帕霉素或其他mTOR抑制剂对抑制mTOR有较好的效果。因此，雷帕霉素和其他靶向mTOR抑制剂可能是治疗这些疾病的潜在候选药物。

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