簡易檢索 / 詳目顯示

回結果列表
研究生： 洪嘉鴻
Hung, Jia-Horung
論文名稱： TIMP3/Wnt軸調節繆氏神經膠細胞之膠樣變性
TIMP3/Wnt axis regulates gliosis of Müller glia
指導教授： 吳梨華
Wu, Li-Wha
許聖民
Hsu, Sheng-Min
蔡坤哲
Tsai, Kuen-Jer
學位類別： 博士
Doctor
系所名稱： 醫學院 - 臨床醫學研究所
Institute of Clinical Medicine
論文出版年： 2025
畢業學年度： 113
語文別： 英文
論文頁數： 103
中文關鍵詞： Müller氏神經膠細胞 、膠樣變性 、金屬蛋白酶組織抑制劑-3 、Wnt通路 、玻璃體樣本 、蛋白分析
外文關鍵詞： Müller glial cells, gliosis, TIMP3, Wnt pathway, vitreous samples, protein analysis
相關次數： 點閱：41  下載：4 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報

    • 背景：先前的研究已確認金屬蛋白酶組織抑制劑-3（TIMP3）在繆氏神經膠細胞（Müller glial, MG）中的表現。然而，TIMP3在MG中的功能仍不明確。

    方法：本研究使用野生型C57BL/6小鼠建立雷射誘導的視網膜損傷和膠質增生(Gliosis)模型，再通過西方墨點法（Western blotting）、免疫螢光顯微術和視網膜-脈絡膜平展染色檢測TIMP3及相關蛋白。在人類繆氏神經膠細胞（MIO-M1細胞株）中誘導TIMP3過度表達。收集增殖性糖尿病視網膜病變（PDR）患者和正常對照的玻璃體樣本進行蛋白分析。

    結果：小鼠眼睛在雷射損傷後TIMP3表達增加，其形態和空間分佈顯示存在於繆氏神經膠細胞中。在機械力損傷之繆氏神經膠細胞模型中，TIMP3表現量增加；TIMP3過度表達的繆氏神經膠細胞顯示細胞增殖、遷移能力以及細胞核大小均增加，表明其參與膠質增生過程並在視網膜修復中發揮作用。TIMP3過度表達的繆氏神經膠細胞和雷射損傷的小鼠視網膜中，Glial fibrillary acidic protein (GFAP) 和Vimentin表現量均升高。利用RNA定序發現TIMP3通過β-catenin參與調節視網膜功能。Western blot結果與qPCR驗證了是藉由Wnt途徑引發β-catenin上升。在PDR患者的玻璃體樣本中，與正常對照組玻璃體相比，TIMP3和GFAP濃度呈正相關，且在患者眼中均顯著升高。

    結論：TIMP3與繆氏神經膠細胞的膠質增生相關，可增強受損視網膜的修復能力，並通過典型Wnt/β-catenin通路調節。TIMP3的變化有可能用於控制多種視網膜疾病中的膠質增生，與其抑制蛋白酶及抗血管生成的既定作用相結合。然而，鑒於TIMP3的多面性，在設計以單純增強TIMP3功能為目標的治療時需謹慎考量。

    Background: Previous studies have confirmed the expression of tissue inhibitors of metalloproteinase-3 (TIMP3) in Müller glial (MG) cells. However, the function of TIMP3 of MG remains unclear.

    Methods: A mouse model of laser-induced retinal injury and gliosis was generated in wild-type C57BL/6 mice. TIMP3 and associated proteins were detected by Western blotting, immunofluorescence microscopy and retino-choroidal flat-mount. TIMP3 overexpression was induced in a human MIO-M1 cell line. Human vitreous samples from proliferative diabetic retinopathy (PDR) and normal controls were obtained for protein analysis.

    Results: TIMP3 increased in mouse eyes after laser damage. Its morphology and spatial location showed its presence in the MG. Similarly, in a mechanical injury model of MG cells, TIMP3 expression was also elevated. TIMP3 over-expressing MG had increased cellular proliferation, cellular migration, and the size of cell nuclei. This suggests the process of gliosis and functioning in the repair of the retina. Glial fibrillary acidic protein (GFAP) and vimentin were elevated in TIMP3-overexpressing MG and in the lasered damaged mouse retina. RNA sequencing and Western blotting suggests a role for Wnt/β-catenin in mediating TIMP3 effects in the retina. Human vitreous samples from PDR patients showed a positive correlation between TIMP3 and GFAP concentrations, both of which were also elevated in the patient eyes with PDR.

    Conclusions: TIMP3 is associated with MG gliosis to enhance the repair ability of damaged retinas and is mediated by the canonical Wnt/β-catenin. Changes in TIMP3 could potentially be used as a treatment to control gliosis in a range of retinal diseases, alongside its established roles in inhibiting proteinase and preventing angiogenesis. However, given the multifaceted nature of TIMP3, care must be taken when creating treatments that solely aim to boost the function of TIMP3.

    I. Certification 2 II. Chinese abstract 3 III. English abstract 4 IV. Acknowledgements 5 V. Table of Contents 7 VI. Table Index 10 VII. Figure Index 11 VIII. Abbreviations 13 Chapter 1. Introduction and Literature Review 15 1.1 Vision and Retina 15 1.2 Müller glia and its function 15 1.3 Gliosis of Müller glia 16 1.4 Tissue inhibitor of metalloproteinase-3 (TIMP3) 17 1.5 TIMP3 and human ocular diseases 18 1.6 MG express TIMP3 20 Chapter 2. Hypothesis 21 Chapter 3. Specific Aims and Rationales 22 Chapter 4. Material and Methods 24 4.1 Ethics 24 4.2 Culture condition of the human MG cells 24 4.3 Plasmids construction, cell transfection, and stable cell line establishment 24 4.4 Western blotting 25 4.5 Separation of nuclear and cytoplasmic protein fractions 25 4.6 Immunofluorescence staining and immunofluorocytochemistry 26 4.7 Cell proliferation assay 26 4.8 Migration assay 27 4.9 Colony formation assay 27 4.10 Cellular injury assay 27 4.11 Small interfering RNA (siRNA) assay 28 4.12 RNA extraction and reverse-transcription real-time quantitative PCR (RT-qPCR) 28 4.13 RNA sequencing data analysis from a public domain dataset 28 4.14 Laser-induced CNV retinal damage and gliosis model in mice 29 4.15 Visualization of protein in mouse retina section by immunofluorescent staining 30 4.16 Visualization of gene expression in mouse retina section by in situ hybridization 31 4.17 IHC for retinal section 32 4.18 Retinochoroidal flat-mount 32 4.19 Human vitreous sampling and target protein quantification 33 4.20 Statistics 33 Chapter 5. Results 35 5.1 TIMP3 expression was upregulated following laser-induced retinal injury 35 5.2 TIMP3 protein and mRNA’s spatial distribution is highly correlated with MG 36 5.3 TIMP3 is correlated with GFAP elevation in laser-induced retinal damage 37 5.4 TIMP3 upregulation in a mechanical cellular injury model 37 5.5 MIO-M1 cells (human MG) with TIMP3 overexpression exhibits increased proliferation, migration, and nuclear hypertrophy 38 5.6 TIMP3 upregulates the expression of GFAP and vimentin 39 5.7. β-catenin pathway mediates laser-induced Timp3 elevation and gliosis 39 5.8 TIMP3 upregulation activates the Wnt/β-catenin canonical pathway, reversible by TIMP3 knockdown 40 5.9 Human vitreous of PDR contains elevated TIMP3 level which is positively correlated with elevated GFAP level 40 Chapter 6. Discussion 42 6.1 Main findings of the study 42 6.2 Significance of TIMP3 in MG 43 6.3 TIMP3 in different retinal cell types 46 6.4 Clinical implications and translation 46 6.5 Strength and limitations 48 6.6 Challenges encountered in this study and future directions 48 6.7 Conclusions 51 Chapter 7. References 52 Chapter 8. Tables 72 Chapter 9. Figures 76

    1. Newman E, Reichenbach A. The Müller cell: a functional element of the retina. Trends Neurosci 1996;19(8):307-12. (In eng). DOI: 10.1016/0166-2236(96)10040-0.
    2. Bringmann A, Pannicke T, Grosche J, et al. Müller cells in the healthy and diseased retina. Prog Retin Eye Res 2006;25(4):397-424. (In eng). DOI: 10.1016/j.preteyeres.2006.05.003.
    3. Kugler EC, Greenwood J, MacDonald RB. The "Neuro-Glial-Vascular" Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction. Front Cell Dev Biol 2021;9:732820. (In eng). DOI: 10.3389/fcell.2021.732820.
    4. Bringmann A, Iandiev I, Pannicke T, et al. Cellular signaling and factors involved in Müller cell gliosis: neuroprotective and detrimental effects. Prog Retin Eye Res 2009;28(6):423-51. (In eng). DOI: 10.1016/j.preteyeres.2009.07.001.
    5. Iandiev I, Uckermann O, Pannicke T, et al. Glial cell reactivity in a porcine model of retinal detachment. Invest Ophthalmol Vis Sci 2006;47(5):2161-71. (In eng). DOI: 10.1167/iovs.05-0595.
    6. Franze K, Grosche J, Skatchkov SN, et al. Muller cells are living optical fibers in the vertebrate retina. Proc Natl Acad Sci U S A 2007;104(20):8287-92. (In eng). DOI: 10.1073/pnas.0611180104.
    7. Lamas M, Martinez-Colin EJ. Müller Cell Molecular Heterogeneity: Facts and Predictions. ASN Neuro 2022;14:17590914221106903. (In eng). DOI: 10.1177/17590914221106903.
    8. Pfeiffer RL, Marc RE, Jones BW. Müller Cell Metabolic Signatures: Evolutionary Conservation and Disruption in Disease. Trends Endocrinol Metab 2020;31(4):320-329. (In eng). DOI: 10.1016/j.tem.2020.01.005.
    9. Luna G, Lewis GP, Banna CD, Skalli O, Fisher SK. Expression profiles of nestin and synemin in reactive astrocytes and Müller cells following retinal injury: a comparison with glial fibrillar acidic protein and vimentin. Mol Vis 2010;16:2511-23. (In eng).
    10. Liu B, He J, Zhong L, et al. Single-cell transcriptome reveals diversity of Müller cells with different metabolic-mitochondrial signatures in normal and degenerated macula. Front Neurosci 2022;16:1079498. (In eng). DOI: 10.3389/fnins.2022.1079498.
    11. Uga S, Smelser. Comparative study of the fine structure of retinal Müller cells in various vertebrates. Invest Ophthalmol 1973;12(6):434-48. (In eng).
    12. Chao TI, Grosche J, Friedrich KJ, et al. Comparative studies on mammalian Müller (retinal glial) cells. J Neurocytol 1997;26(7):439-54. (In eng). DOI: 10.1023/a:1018525222826.
    13. Distler C, Dreher Z. Glia cells of the monkey retina--II. Müller cells. Vision Res 1996;36(16):2381-94. (In eng). DOI: 10.1016/0042-6989(96)00005-3.
    14. Lenkowski JR, Raymond PA. Müller glia: Stem cells for generation and regeneration of retinal neurons in teleost fish. Prog Retin Eye Res 2014;40:94-123. (In eng). DOI: 10.1016/j.preteyeres.2013.12.007.
    15. Goldman D. Muller glial cell reprogramming and retina regeneration. Nat Rev Neurosci 2014;15(7):431-42. DOI: 10.1038/nrn3723.
    16. Devoldere J, Peynshaert K, De Smedt SC, Remaut K. Müller cells as a target for retinal therapy. Drug Discov Today 2019;24(8):1483-1498. (In eng). DOI: 10.1016/j.drudis.2019.01.023.
    17. Navneet S, Wilson K, Rohrer B. Müller Glial Cells in the Macula: Their Activation and Cell-Cell Interactions in Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2024;65(2):42. (In eng). DOI: 10.1167/iovs.65.2.42.
    18. Caicedo A, Espinosa-Heidmann DG, Pina Y, Hernandez EP, Cousins SW. Blood-derived macrophages infiltrate the retina and activate Muller glial cells under experimental choroidal neovascularization. Exp Eye Res 2005;81(1):38-47. DOI: 10.1016/j.exer.2005.01.013.
    19. Ishida T, Yoshida T, Shinohara K, et al. Potential role of sirtuin 1 in Müller glial cells in mice choroidal neovascularization. PLoS One 2017;12(9):e0183775. (In eng). DOI: 10.1371/journal.pone.0183775.
    20. Sardar Pasha SPB, Münch R, Schäfer P, et al. Retinal cell death dependent reactive proliferative gliosis in the mouse retina. Sci Rep 2017;7(1):9517. (In eng). DOI: 10.1038/s41598-017-09743-8.
    21. Vecino E, Rodriguez FD, Ruzafa N, Pereiro X, Sharma SC. Glia-neuron interactions in the mammalian retina. Prog Retin Eye Res 2016;51:1-40. (In eng). DOI: 10.1016/j.preteyeres.2015.06.003.
    22. de Melo J, Miki K, Rattner A, et al. Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2. Proc Natl Acad Sci U S A 2012;109(12):4657-62. (In eng). DOI: 10.1073/pnas.1107488109.
    23. Wang M, Ma W, Zhao L, Fariss RN, Wong WT. Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina. J Neuroinflammation 2011;8:173. (In eng). DOI: 10.1186/1742-2094-8-173.
    24. Matsumoto H, Sugio S, Seghers F, et al. Retinal Detachment-Induced Müller Glial Cell Swelling Activates TRPV4 Ion Channels and Triggers Photoreceptor Death at Body Temperature. J Neurosci 2018;38(41):8745-8758. (In eng). DOI: 10.1523/jneurosci.0897-18.2018.
    25. Shiode Y, Morizane Y, Matoba R, et al. The Role of Inverted Internal Limiting Membrane Flap in Macular Hole Closure. Invest Ophthalmol Vis Sci 2017;58(11):4847-4855. (In eng). DOI: 10.1167/iovs.17-21756.
    26. Li Q, Cheng Y, Zhang S, Sun X, Wu J. TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway. J Neuroinflammation 2021;18(1):271. (In eng). DOI: 10.1186/s12974-021-02315-8.
    27. Tomita Y, Qiu C, Bull E, et al. Müller glial responses compensate for degenerating photoreceptors in retinitis pigmentosa. Exp Mol Med 2021;53(11):1748-1758. (In eng). DOI: 10.1038/s12276-021-00693-w.
    28. Li M, Huisingh C, Messinger J, et al. HISTOLOGY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION: A Multilayer Approach. Retina 2018;38(10):1937-1953. (In eng). DOI: 10.1097/iae.0000000000002182.
    29. Wu KH, Madigan MC, Billson FA, Penfold PL. Differential expression of GFAP in early v late AMD: a quantitative analysis. Br J Ophthalmol 2003;87(9):1159-66. (In eng). DOI: 10.1136/bjo.87.9.1159.
    30. Li M, Dolz-Marco R, Messinger JD, Ferrara D, Freund KB, Curcio CA. Neurodegeneration, gliosis, and resolution of haemorrhage in neovascular age-related macular degeneration, a clinicopathologic correlation. Eye (Lond) 2021;35(2):548-558. (In eng). DOI: 10.1038/s41433-020-0896-y.
    31. Rungger-Brändle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci 2000;41(7):1971-80. (In eng).
    32. Llorián-Salvador M, Cabeza-Fernández S, Gomez-Sanchez JA, de la Fuente AG. Glial cell alterations in diabetes-induced neurodegeneration. Cell Mol Life Sci 2024;81(1):47. (In eng). DOI: 10.1007/s00018-023-05024-y.
    33. Amin RH, Frank RN, Kennedy A, Eliott D, Puklin JE, Abrams GW. Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 1997;38(1):36-47. (In eng).
    34. Pardue MT, Stubbs EB, Jr., Perlman JI, Narfström K, Chow AY, Peachey NS. Immunohistochemical studies of the retina following long-term implantation with subretinal microphotodiode arrays. Exp Eye Res 2001;73(3):333-43. (In eng). DOI: 10.1006/exer.2001.1041.
    35. Calame M, Cachafeiro M, Philippe S, et al. Retinal degeneration progression changes lentiviral vector cell targeting in the retina. PLoS One 2011;6(8):e23782. (In eng). DOI: 10.1371/journal.pone.0023782.
    36. Kinouchi R, Takeda M, Yang L, et al. Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin. Nat Neurosci 2003;6(8):863-8. (In eng). DOI: 10.1038/nn1088.
    37. Jackson HW, Defamie V, Waterhouse P, Khokha R. TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer 2017;17(1):38-53. (In eng). DOI: 10.1038/nrc.2016.115.
    38. Hussain AA, Lee Y, Marshall J. Understanding the complexity of the matrix metalloproteinase system and its relevance to age-related diseases: Age-related macular degeneration and Alzheimer's disease. Prog Retin Eye Res 2020;74:100775. (In eng). DOI: 10.1016/j.preteyeres.2019.100775.
    39. Qi JH, Bell B, Singh R, et al. Sorsby Fundus Dystrophy Mutation in Tissue Inhibitor of Metalloproteinase 3 (TIMP3) promotes Choroidal Neovascularization via a Fibroblast Growth Factor-dependent Mechanism. Sci Rep 2019;9(1):17429. (In eng). DOI: 10.1038/s41598-019-53433-6.
    40. Weber BH, Vogt G, Pruett RC, Stöhr H, Felbor U. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat Genet 1994;8(4):352-6. (In eng). DOI: 10.1038/ng1294-352.
    41. Guan B, Huryn LA, Hughes AB, et al. Early-Onset TIMP3-Related Retinopathy Associated With Impaired Signal Peptide. JAMA Ophthalmol 2022 (In eng). DOI: 10.1001/jamaophthalmol.2022.1822.
    42. Chen W, Stambolian D, Edwards AO, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A 2010;107(16):7401-6. (In eng). DOI: 10.1073/pnas.0912702107.
    43. Fritsche LG, Igl W, Bailey JN, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet 2016;48(2):134-43. (In eng). DOI: 10.1038/ng.3448.
    44. The Eye Diseases Prevalence Research G. Causes and prevalence of visual impairment among adults in the united states. Archives of Ophthalmology 2004;122(4):477-485. DOI: 10.1001/archopht.122.4.477.
    45. Klenotic PA, Munier FL, Marmorstein LY, Anand-Apte B. Tissue Inhibitor of Metalloproteinases-3 (TIMP-3) Is a Binding Partner of Epithelial Growth Factor-containing Fibulin-like Extracellular Matrix Protein 1 (EFEMP1): IMPLICATIONS FOR MACULAR DEGENERATIONS. Journal of Biological Chemistry 2004;279(29):30469-30473. DOI: 10.1074/jbc.M403026200.
    46. Yu WH, Yu S, Meng Q, Brew K, Woessner JF, Jr. TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. J Biol Chem 2000;275(40):31226-32. (In eng). DOI: 10.1074/jbc.M000907200.
    47. Wilde CG, Hawkins PR, Coleman RT, et al. Cloning and characterization of human tissue inhibitor of metalloproteinases-3. DNA Cell Biol 1994;13(7):711-8. (In eng). DOI: 10.1089/dna.1994.13.711.
    48. Betts JHJ, Troeberg L. Review: Mechanisms of TIMP-3 accumulation and pathogenesis in Sorsby fundus dystrophy. Mol Vis 2024;30:74-91. (In eng).
    49. Guan Z, Zhang J, Song S, Dai D. Promoter methylation and expression of TIMP3 gene in gastric cancer. Diagn Pathol 2013;8:110. (In eng). DOI: 10.1186/1746-1596-8-110.
    50. Su CW, Chang YC, Chien MH, et al. Loss of TIMP3 by promoter methylation of Sp1 binding site promotes oral cancer metastasis. Cell Death Dis 2019;10(11):793. (In eng). DOI: 10.1038/s41419-019-2016-0.
    51. Wick M, Härönen R, Mumberg D, et al. Structure of the human TIMP-3 gene and its cell cycle-regulated promoter. Biochem J 1995;311 ( Pt 2)(Pt 2):549-54. (In eng). DOI: 10.1042/bj3110549.
    52. Park S, Kim K, Bae IH, et al. TIMP3 is a CLOCK-dependent diurnal gene that inhibits the expression of UVB-induced inflammatory cytokines in human keratinocytes. Faseb j 2018;32(3):1510-1523. (In eng). DOI: 10.1096/fj.201700693R.
    53. Scilabra SD, Troeberg L, Yamamoto K, et al. Differential regulation of extracellular tissue inhibitor of metalloproteinases-3 levels by cell membrane-bound and shed low density lipoprotein receptor-related protein 1. J Biol Chem 2013;288(1):332-42. (In eng). DOI: 10.1074/jbc.M112.393322.
    54. Hu J, Ni S, Cao Y, et al. The Angiogenic Effect of microRNA-21 Targeting TIMP3 through the Regulation of MMP2 and MMP9. PLoS One 2016;11(2):e0149537. (In eng). DOI: 10.1371/journal.pone.0149537.
    55. Di Gregoli K, Mohamad Anuar NN, Bianco R, et al. MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin. Circ Res 2017;120(1):49-65. (In eng). DOI: 10.1161/circresaha.116.309321.
    56. Gan R, Yang Y, Yang X, Zhao L, Lu J, Meng QH. Downregulation of miR-221/222 enhances sensitivity of breast cancer cells to tamoxifen through upregulation of TIMP3. Cancer Gene Ther 2014;21(7):290-6. (In eng). DOI: 10.1038/cgt.2014.29.
    57. Jiang C, Xia W, Wu T, et al. Inhibition of microRNA-222 up-regulates TIMP3 to promotes osteogenic differentiation of MSCs from fracture rats with type 2 diabetes mellitus. J Cell Mol Med 2020;24(1):686-694. (In eng). DOI: 10.1111/jcmm.14777.
    58. Wang J, Zhang J, Chen X, et al. miR-365 promotes diabetic retinopathy through inhibiting Timp3 and increasing oxidative stress. Exp Eye Res 2018;168:89-99. (In eng). DOI: 10.1016/j.exer.2017.11.006.
    59. Lan J, Kumar RK, Di Girolamo N, McCluskey P, Wakefield D. Expression and distribution of matrix metalloproteinases and their inhibitors in the human iris and ciliary body. Br J Ophthalmol 2003;87(2):208-11. (In eng). DOI: 10.1136/bjo.87.2.208.
    60. Ruiz A, Brett P, Bok D. TIMP-3 is expressed in the human retinal pigment epithelium. Biochem Biophys Res Commun 1996;226(2):467-74. (In eng). DOI: 10.1006/bbrc.1996.1379.
    61. Della NG, Campochiaro PA, Zack DJ. Localization of TIMP-3 mRNA expression to the retinal pigment epithelium. Invest Ophthalmol Vis Sci 1996;37(9):1921-4. (In eng).
    62. Fariss RN, Apte SS, Olsen BR, Iwata K, Milam AH. Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye. Am J Pathol 1997;150(1):323-8. (In eng).
    63. Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002;115(Pt 19):3719-27. (In eng). DOI: 10.1242/jcs.00063.
    64. Qi JH, Ebrahem Q, Moore N, et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 2003;9(4):407-15. (In eng). DOI: 10.1038/nm846.
    65. Su CW, Lin CW, Yang WE, Yang SF. TIMP-3 as a therapeutic target for cancer. Ther Adv Med Oncol 2019;11:1758835919864247. (In eng). DOI: 10.1177/1758835919864247.
    66. Manousopoulou A, Gatherer M, Smith C, et al. Systems proteomic analysis reveals that clusterin and tissue inhibitor of metalloproteinases 3 increase in leptomeningeal arteries affected by cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 2017;43(6):492-504. (In eng). DOI: 10.1111/nan.12342.
    67. Hsu WM, Cheng CY, Liu JH, Tsai SY, Chou P. Prevalence and causes of visual impairment in an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology 2004;111(1):62-9. DOI: 10.1016/j.ophtha.2003.05.011.
    68. Flaxman SR, Bourne RRA, Resnikoff S, et al. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis. Lancet Glob Health 2017;5(12):e1221-e1234. DOI: 10.1016/S2214-109X(17)30393-5.
    69. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2014;2(2):e106-16. (In eng). DOI: 10.1016/s2214-109x(13)70145-1.
    70. Black JR, Clark SJ. Age-related macular degeneration: genome-wide association studies to translation. Genet Med 2016;18(4):283-9. DOI: 10.1038/gim.2015.70.
    71. Cascella R, Strafella C, Caputo V, et al. Towards the application of precision medicine in Age-Related Macular Degeneration. Prog Retin Eye Res 2018;63:132-146. DOI: 10.1016/j.preteyeres.2017.11.004.
    72. De La Paz MA, Pericak-Vance MA, Lennon F, Haines JL, Seddon JM. Exclusion of TIMP3 as a candidate locus in age-related macular degeneration. Invest Ophthalmol Vis Sci 1997;38(6):1060-5. (In eng).
    73. Zeng R, Wen F, Zhang X, et al. An rs9621532 variant near the TIMP3 gene is not associated with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in a Chinese Han population. Ophthalmic Genet 2012;33(3):139-43. (In eng). DOI: 10.3109/13816810.2011.643440.
    74. Grenell A, Singh C, Raju M, et al. Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells. Mol Metab 2024;88:101995. (In eng). DOI: 10.1016/j.molmet.2024.101995.
    75. Anand-Apte B, Chao JR, Singh R, Stöhr H. Sorsby fundus dystrophy: Insights from the past and looking to the future. J Neurosci Res 2019;97(1):88-97. (In eng). DOI: 10.1002/jnr.24317.
    76. Qi JH, Ebrahem Q, Ali M, et al. Tissue inhibitor of metalloproteinases-3 peptides inhibit angiogenesis and choroidal neovascularization in mice. PLoS One 2013;8(3):e55667. DOI: 10.1371/journal.pone.0055667.
    77. Menon M, Mohammadi S, Davila-Velderrain J, et al. Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration. Nat Commun 2019;10(1):4902. (In eng). DOI: 10.1038/s41467-019-12780-8.
    78. Limb GA, Salt TE, Munro PM, Moss SE, Khaw PT. In vitro characterization of a spontaneously immortalized human Müller cell line (MIO-M1). Invest Ophthalmol Vis Sci 2002;43(3):864-9. (In eng).
    79. Fan J, Schiemer T, Vaska A, Jahed V, Klavins K. Cell via Cell Viability Assay Changes Cellular Metabolic Characteristics by Intervening with Glycolysis and Pentose Phosphate Pathway. Chem Res Toxicol 2024;37(2):208-211. (In eng). DOI: 10.1021/acs.chemrestox.3c00339.
    80. Lu D, Wang Y, Liu G, et al. Armcx1 attenuates secondary brain injury in an experimental traumatic brain injury model in male mice by alleviating mitochondrial dysfunction and neuronal cell death. Neurobiol Dis 2023;184:106228. (In eng). DOI: 10.1016/j.nbd.2023.106228.
    81. Bae YH, Joo H, Bae J, et al. Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage. Cell Death Dis 2018;9(11):1125. (In eng). DOI: 10.1038/s41419-018-1180-y.
    82. Yeh WJ, Chien PT, Wen YT, Wu CH. A comprehensive review of experimental models for investigating blue light-induced ocular damage: Insights into parameters, limitations, and new opportunities. Exp Eye Res 2024;249:110142. (In eng). DOI: 10.1016/j.exer.2024.110142.
    83. Conedera FM, Pousa AMQ, Mercader N, Tschopp M, Enzmann V. The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar. Mol Neurodegener 2021;16(1):69. (In eng). DOI: 10.1186/s13024-021-00482-z.
    84. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15(12):550. (In eng). DOI: 10.1186/s13059-014-0550-8.
    85. Chen EY, Tan CM, Kou Y, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 2013;14(1):128. DOI: 10.1186/1471-2105-14-128.
    86. Kuleshov MV, Jones MR, Rouillard AD, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 2016;44(W1):W90-7. (In eng). DOI: 10.1093/nar/gkw377.
    87. Xie Z, Bailey A, Kuleshov MV, et al. Gene Set Knowledge Discovery with Enrichr. Current Protocols 2021;1(3):e90. DOI: https://doi.org/10.1002/cpz1.90.
    88. Fiorentino L, Cavalera M, Menini S, et al. Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO Mol Med 2013;5(3):441-55. (In eng). DOI: 10.1002/emmm.201201475.
    89. Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003;13(11):2498-504. (In eng). DOI: 10.1101/gr.1239303.
    90. Gong Y, Li J, Sun Y, et al. Optimization of an Image-Guided Laser-Induced Choroidal Neovascularization Model in Mice. PLOS ONE 2015;10(7):e0132643. DOI: 10.1371/journal.pone.0132643.
    91. Benton RL, Maddie MA, Minnillo DR, Hagg T, Whittemore SR. Griffonia simplicifolia isolectin B4 identifies a specific subpopulation of angiogenic blood vessels following contusive spinal cord injury in the adult mouse. J Comp Neurol 2008;507(1):1031-52. (In eng). DOI: 10.1002/cne.21570.
    92. Campos M, Amaral J, Becerra SP, Fariss RN. A novel imaging technique for experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 2006;47(12):5163-70. (In eng). DOI: 10.1167/iovs.06-0156.
    93. Wang X, Wang H, Wang J, et al. Single-shot isotropic differential interference contrast microscopy. Nat Commun 2023;14(1):2063. (In eng). DOI: 10.1038/s41467-023-37606-6.
    94. Tran NM, Shekhar K, Whitney IE, et al. Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to Injury Reveal Neuroprotective Genes. Neuron 2019;104(6):1039-1055.e12. (In eng). DOI: 10.1016/j.neuron.2019.11.006.
    95. Lambert V, Lecomte J, Hansen S, et al. Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice. Nature Protocols 2013;8(11):2197-2211. DOI: 10.1038/nprot.2013.135.
    96. Ghodasra DH, Fante R, Gardner TW, et al. Safety and Feasibility of Quantitative Multiplexed Cytokine Analysis From Office-Based Vitreous Aspiration. Invest Ophthalmol Vis Sci 2016;57(7):3017-23. (In eng). DOI: 10.1167/iovs.15-18721.
    97. Trapecar M, Wogram E, Svoboda D, et al. Human physiomimetic model integrating microphysiological systems of the gut, liver, and brain for studies of neurodegenerative diseases. Sci Adv 2021;7(5) (In eng). DOI: 10.1126/sciadv.abd1707.
    98. R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2023.
    99. Hisatomi T, Sakamoto T, Yamanaka I, et al. Photocoagulation-induced retinal gliosis is inhibited by systemically expressed soluble TGF-beta receptor type II via adenovirus mediated gene transfer. Lab Invest 2002;82(7):863-70. (In eng). DOI: 10.1097/01.lab.0000018829.49754.dd.
    100. Giani A, Thanos A, Roh MI, et al. In vivo evaluation of laser-induced choroidal neovascularization using spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 2011;52(6):3880-7. (In eng). DOI: 10.1167/iovs.10-6266.
    101. Matsuo T, Okada Y, Shiraga F, Yanagawa T. TIMP-1 and TIMP-2 levels in vitreous and subretinal fluid. Jpn J Ophthalmol 1998;42(5):377-80. (In eng). DOI: 10.1016/s0021-5155(98)00038-0.
    102. Abu El-Asrar AM, Ahmad A, Bittoun E, et al. Differential expression and localization of human tissue inhibitors of metalloproteinases in proliferative diabetic retinopathy. Acta Ophthalmol 2018;96(1):e27-e37. (In eng). DOI: 10.1111/aos.13451.
    103. Jünemann AG, Rejdak R, Huchzermeyer C, et al. Elevated vitreous body glial fibrillary acidic protein in retinal diseases. Graefes Arch Clin Exp Ophthalmol 2015;253(12):2181-6. (In eng). DOI: 10.1007/s00417-015-3127-7.
    104. Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 1994;269(12):9352-60. (In eng).
    105. Hakamy S, Assidi M, Jafri MA, et al. Assessment of prognostic value of tissue inhibitors of metalloproteinase 3 (TIMP3) protein in ovarian cancer. Libyan J Med 2021;16(1):1937866. (In eng). DOI: 10.1080/19932820.2021.1937866.
    106. Masson D, Rioux-Leclercq N, Fergelot P, et al. Loss of expression of TIMP3 in clear cell renal cell carcinoma. Eur J Cancer 2010;46(8):1430-7. (In eng). DOI: 10.1016/j.ejca.2010.01.009.
    107. Mylona E, Magkou C, Giannopoulou I, et al. Expression of tissue inhibitor of matrix metalloproteinases (TIMP)-3 protein in invasive breast carcinoma: relation to tumor phenotype and clinical outcome. Breast Cancer Res 2006;8(5):R57. (In eng). DOI: 10.1186/bcr1607.
    108. Carreca AP, Pravatà VM, Markham M, et al. TIMP-3 facilitates binding of target metalloproteinases to the endocytic receptor LRP-1 and promotes scavenging of MMP-1. Sci Rep 2020;10(1):12067. (In eng). DOI: 10.1038/s41598-020-69008-9.
    109. Lei Y, Liu Z, Yang W. Negative correlation of cytoplasm TIMP3 with miR-222 indicates a good prognosis for NSCLC. Onco Targets Ther 2018;11:5551-5557. (In eng). DOI: 10.2147/ott.S172522.
    110. Janssen A, Hoellenriegel J, Fogarasi M, et al. Abnormal vessel formation in the choroid of mice lacking tissue inhibitor of metalloprotease-3. Invest Ophthalmol Vis Sci 2008;49(7):2812-22. (In eng). DOI: 10.1167/iovs.07-1444.
    111. Macgregor AM, Eberhart CG, Fraig M, Lu J, Halushka MK. Tissue inhibitor of matrix metalloproteinase-3 levels in the extracellular matrix of lung, kidney, and eye increase with age. J Histochem Cytochem 2009;57(3):207-13. (In eng). DOI: 10.1369/jhc.2008.952531.
    112. Amour A, Slocombe PM, Webster A, et al. TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett 1998;435(1):39-44. (In eng). DOI: 10.1016/s0014-5793(98)01031-x.
    113. Wisniewska M, Goettig P, Maskos K, et al. Structural determinants of the ADAM inhibition by TIMP-3: crystal structure of the TACE-N-TIMP-3 complex. J Mol Biol 2008;381(5):1307-19. (In eng). DOI: 10.1016/j.jmb.2008.06.088.
    114. Ramana KV. Tumor necrosis factor-alpha converting enzyme: Implications for ocular inflammatory diseases. Int J Biochem Cell Biol 2010;42(7):1076-9. (In eng). DOI: 10.1016/j.biocel.2010.03.011.
    115. Sunnarborg SW, Hinkle CL, Stevenson M, et al. Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J Biol Chem 2002;277(15):12838-45. (In eng). DOI: 10.1074/jbc.M112050200.
    116. Abu El-Asrar AM, Ahmad A, Nawaz MI, et al. Tissue Inhibitor of Metalloproteinase-3 Ameliorates Diabetes-Induced Retinal Inflammation. Front Physiol 2021;12:807747. (In eng). DOI: 10.3389/fphys.2021.807747.
    117. Vohra R, Kolko M. Neuroprotection of the inner retina: Müller cells and lactate. Neural Regen Res 2018;13(10):1741-1742. (In eng). DOI: 10.4103/1673-5374.238612.
    118. Tassoni A, Gutteridge A, Barber AC, Osborne A, Martin KR. Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation. Stem Cells 2015;33(10):3006-16. (In eng). DOI: 10.1002/stem.2095.
    119. Lahne M, Nagashima M, Hyde DR, Hitchcock PF. Reprogramming Müller Glia to Regenerate Retinal Neurons. Annu Rev Vis Sci 2020;6:171-193. (In eng). DOI: 10.1146/annurev-vision-121219-081808.
    120. Bradbury EJ, Burnside ER. Moving beyond the glial scar for spinal cord repair. Nat Commun 2019;10(1):3879. (In eng). DOI: 10.1038/s41467-019-11707-7.
    121. Liu B, Hunter DJ, Rooker S, et al. Wnt signaling promotes Müller cell proliferation and survival after injury. Invest Ophthalmol Vis Sci 2013;54(1):444-53. (In eng). DOI: 10.1167/iovs.12-10774.
    122. Yao K, Qiu S, Tian L, et al. Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas. Cell Reports 2016;17(1):165-178. DOI: https://doi.org/10.1016/j.celrep.2016.08.078.
    123. Gao L, Chen B, Li J, et al. Wnt/β-catenin signaling pathway inhibits the proliferation and apoptosis of U87 glioma cells via different mechanisms. PLoS One 2017;12(8):e0181346. (In eng). DOI: 10.1371/journal.pone.0181346.
    124. Sanges D, Romo N, Simonte G, et al. Wnt/β-catenin signaling triggers neuron reprogramming and regeneration in the mouse retina. Cell Rep 2013;4(2):271-86. (In eng). DOI: 10.1016/j.celrep.2013.06.015.
    125. Hoang T, Wang J, Boyd P, et al. Gene regulatory networks controlling vertebrate retinal regeneration. Science 2020;370(6519) (In eng). DOI: 10.1126/science.abb8598.
    126. Rudraraju M, Shan S, Liu F, et al. Pharmacological Modulation of β-Catenin Preserves Endothelial Barrier Integrity and Mitigates Retinal Vascular Permeability and Inflammation. J Clin Med 2023;12(22) (In eng). DOI: 10.3390/jcm12227145.
    127. Boesl F, Drexler K, Müller B, et al. Endogenous Wnt/β-catenin signaling in Müller cells protects retinal ganglion cells from excitotoxic damage. Mol Vis 2020;26:135-149. (In eng).
    128. Chidlow G, Shibeeb O, Plunkett M, Casson RJ, Wood JP. Glial cell and inflammatory responses to retinal laser treatment: comparison of a conventional photocoagulator and a novel, 3-nanosecond pulse laser. Invest Ophthalmol Vis Sci 2013;54(3):2319-32. (In eng). DOI: 10.1167/iovs.12-11204.
    129. Pennesi ME, Neuringer M, Courtney RJ. Animal models of age related macular degeneration. Mol Aspects Med 2012;33(4):487-509. (In eng). DOI: 10.1016/j.mam.2012.06.003.
    130. Krigel A, Berdugo M, Picard E, et al. Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity. Neuroscience 2016;339:296-307. (In eng). DOI: 10.1016/j.neuroscience.2016.10.015.
    131. Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2000;45(2):115-34. (In eng). DOI: 10.1016/s0039-6257(00)00140-5.
    132. Upadhyay M, Milliner C, Bell BA, Bonilha VL. Oxidative stress in the retina and retinal pigment epithelium (RPE): Role of aging, and DJ-1. Redox Biology 2020;37:101623. DOI: https://doi.org/10.1016/j.redox.2020.101623.
    133. de Hoz R, Rojas B, Ramírez AI, et al. Retinal Macroglial Responses in Health and Disease. Biomed Res Int 2016;2016:2954721. (In eng). DOI: 10.1155/2016/2954721.
    134. Dalvi S, Roll M, Chatterjee A, et al. Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies. Dev Cell 2024;59(24):3290-3305.e9. (In eng). DOI: 10.1016/j.devcel.2024.09.006.
    135. Qi JH, Ebrahem Q, Yeow K, Edwards DR, Fox PL, Anand-Apte B. Expression of Sorsby's fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis. J Biol Chem 2002;277(16):13394-400. (In eng). DOI: 10.1074/jbc.M110870200.
    136. Engel AL, Wang Y, Khuu TH, et al. Extracellular matrix dysfunction in Sorsby patient-derived retinal pigment epithelium. Exp Eye Res 2022;215:108899. (In eng). DOI: 10.1016/j.exer.2021.108899.
    137. Liu W, Furuichi T, Miyake M, Rosenberg GA, Liu KJ. Differential expression of tissue inhibitor of metalloproteinases-3 in cultured astrocytes and neurons regulates the activation of matrix metalloproteinase-2. J Neurosci Res 2007;85(4):829-36. (In eng). DOI: 10.1002/jnr.21179.
    138. Chang-Lin JE, Attar M, Acheampong AA, et al. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci 2011;52(1):80-6. (In eng). DOI: 10.1167/iovs.10-5285.
    139. Ranade SV, Wieland MR, Tam T, et al. The Port Delivery System with ranibizumab: a new paradigm for long-acting retinal drug delivery. Drug Deliv 2022;29(1):1326-1334. (In eng). DOI: 10.1080/10717544.2022.2069301.
    140. Bordet T, Behar-Cohen F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discov Today 2019;24(8):1685-1693. (In eng). DOI: 10.1016/j.drudis.2019.05.038.
    141. Drag S, Dotiwala F, Upadhyay AK. Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions. Invest Ophthalmol Vis Sci 2023;64(7):39. (In eng). DOI: 10.1167/iovs.64.7.39.
    142. Augustine J, Pavlou S, Harkin K, Stitt AW, Xu H, Chen M. IL-33 regulates Müller cell-mediated retinal inflammation and neurodegeneration in diabetic retinopathy. Disease Models & Mechanisms 2023;16(9). DOI: 10.1242/dmm.050174.
    143. Fujimura N. WNT/β-Catenin Signaling in Vertebrate Eye Development. Front Cell Dev Biol 2016;4:138. (In eng). DOI: 10.3389/fcell.2016.00138.
    144. Shah R, Amador C, Chun ST, et al. Non-canonical Wnt signaling in the eye. Prog Retin Eye Res 2023;95:101149. (In eng). DOI: 10.1016/j.preteyeres.2022.101149.
    145. Fuhrmann S. Wnt signaling in eye organogenesis. Organogenesis 2008;4(2):60-7. (In eng). DOI: 10.4161/org.4.2.5850.
    146. Cadigan KM, Waterman ML. TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 2012;4(11) (In eng). DOI: 10.1101/cshperspect.a007906.
    147. Robinson R, Barathi VA, Chaurasia SS, Wong TY, Kern TS. Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals. Dis Model Mech 2012;5(4):444-56. (In eng). DOI: 10.1242/dmm.009597.
    148. Kumar S, Zhuo L. Longitudinal in vivo imaging of retinal gliosis in a diabetic mouse model. Exp Eye Res 2010;91(4):530-6. (In eng). DOI: 10.1016/j.exer.2010.07.010.
    149. Chang S. LXII Edward Jackson lecture: open angle glaucoma after vitrectomy. Am J Ophthalmol 2006;141(6):1033-1043. (In eng). DOI: 10.1016/j.ajo.2006.02.014.
    150. Del Amo EM, Rimpelä AK, Heikkinen E, et al. Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res 2017;57:134-185. (In eng). DOI: 10.1016/j.preteyeres.2016.12.001.

    下載圖示 校內：立即公開
    校外：立即公開
    QR CODE