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系統識別號 U0026-2001201515583100
論文名稱(中文) 微型核酸-145與-212調控脊髓損傷時星狀膠細胞之功能
論文名稱(英文) MicroRNA-145 and -212 regulate astrocytic function after spinal cord injury
校院名稱 成功大學
系所名稱(中) 生命科學系
系所名稱(英) Department of Life Sciences
學年度 103
學期 1
出版年 104
研究生(中文) 王之彥
研究生(英文) Chih-Yen Wang
學號 L58981014
學位類別 博士
語文別 英文
論文頁數 95頁
口試委員 指導教授-曾淑芬
口試委員-楊重熙
口試委員-鄭宏志
口試委員-許桂森
口試委員-楊尚訓
口試委員-陳柏熹
中文關鍵字 脊髓損傷  星狀膠細胞增生  膠質疤  微型核醣核酸  mir-145  mir-212 
英文關鍵字 Spinal cord injury  Astrogliosis  Glial scar  MicroRNA  mir-145  mir-212 
學科別分類
中文摘要 脊髓損傷後,星狀膠細胞進行大量增生(astrogliosis)以促進神經組織修復,這些星狀膠細胞會幫助與保護神經細胞,並形成膠質疤(glial scar)將受傷處包圍住以防止二次傷害擴散。最近研究發現微型核糖核酸(microRNA)在神經退化疾病與創傷中扮演重要的角色。本研究發現在神經細胞與星狀膠細胞高度表現之microRNA ─ mir-145,在脊髓損傷後一周與一個月的時間點表現量顯著下降。利用細胞實驗發現,給予細菌脂多醣(lipopolysaccharide)誘發發炎訊號,會透過p38 MAPK與ERK1/2訊息傳遞路徑抑制星狀膠細胞中mir-145之表現量。動物實驗則利用慢病毒(lentivirus)轉染脊髓組織,藉GFAP啟動子專一地將mir-145大量表現於星狀膠細胞(其為高度表現GFAP之細胞)。在脊髓損傷位置周圍,高度表現mir-145之星狀膠細胞的數量明顯少於控制組,細胞纖維密度也較低,導致活化之微膠細胞擴散。以細胞實驗觀察,高度表現mir-145之星狀膠細胞的體積降低、延伸觸腳數目變少、生長速度降低、細胞遷移能力也變弱。利用冷光分析實驗(3’-UTR luciferase reporter analysis)與西方點墨法(western blot)確認GFAP與c-myc為mir-145之目標mRNA,推測mir-145可能分別藉由抑制GFAP與c-myc之表現進而影響細胞型態與生長。另外發現星狀膠質細胞麩胺酸轉送蛋白GLAST亦為mir-145之目標mRNA。另一方面,實驗結果顯示在脊髓損傷或星狀膠細胞處理LPS後,mir-212之表現量也下降。而過度表現mir-212會改變星狀膠細胞形態的現象,其可能藉由透過抑制β-actin之表現與組成。綜合以上結果發現,mir-145與mir-212會調控星狀膠細胞的動態表現(dynamics);推測mir-145與mir-212表現下降為脊髓損傷後星狀膠細胞增生與細胞形態變化的重要影響因子。
英文摘要 Astrogliosis is essential for tissue repair after spinal cord injury (SCI), since astrocytes play supporting roles for neurons and form glial scar as a physical barrier to prohibit the expansion of secondary injury. Deregulated microRNAs (miRNAs) have been reported to contribute to CNS neurodegeneration and damages. In this study, we present that mir-145, a miRNA species enriched in rat neurons and astrocytes, was downregulated at the lesion site at 1 week (subacute) and 1 month (chronic) after SCI. The in vitro studies showed that potent inflammagen lipopolysaccharide (LPS) inhibited astrocytic mir-145 expression via p38 MAPK or ERK1/2 pathway. We used lentivirus-mediated pre-miRNA delivery system using the promoter of glial fibrillary acidic protein (GFAP), an astrocyte-specific intermediate filament, to induce astrocyte-specific overexpression of mir-145 at the lesion site. The results indicated that astrocytic mir-145 overexpression attenuated the pileup of astrocytes at the lesion border and reduced their process density, along with the increased accumulation of activated microglia. In parallel, overexpression of mir-145 reduced astrocytic cell size and the number of astrocytic cell processes. Astrocytic cell proliferation and migration were diminished after mir-145 overexpression. Through 3’-UTR luciferase reporter assay and western blot analysis, we identified that GFAP and c-Myc were the direct targets of mir-145 in astrocytes. These findings demonstrate that mir-145 regulates astrocytic dynamics partly via the downregulation of GFAP and c-Myc. In addition, we identified that astrocytic glutamate transporter, GLAST, was one of mir-145 targets.
In the regard to mir-212, the miRNA was observed to be expressed in neurons mainly, but in astrocytes and oligodendrocytes to some degree. Its level was also reduced at the lesion site after SCI. After exposure of astrocytes to LPS, astrocytic mir-212 was downregulated. Overexpression of mir-212 caused the morphological change of astrocytes into elongated process-bearing shapes, which might be due to mir-212 induced repression of β-actin expression.
Together, the results from the study as described above point to the novel role of mir-145 and mir-212 in the regulation of astrocytic dynamics. Moreover, the findings reveal that the downregulation of mir-145 and mir-212 in astrocytes after SCI might be critical for astrogliosis after SCI.
論文目次 致謝 I
中文摘要 II
Abstract III
Abbreviation list X
Introduction 1
Spinal cord and neural cells 2
Spinal cord injury 3
Inflammation 4
Astrogliosis 6
Mir-145 and mir-212-related studies 12
Specific aims 14
Materials and Methods 15
Spinal cord injury 16
Intraspinal injection of lentivirus particles 16
In situ hybridization combined with immunohistochemistry 17
Cell culture preparation 18
Quantitative real-time polymerase chain reaction 19
Lentivirus-mediated overexpression of mir-145 and mir-212 19
Transfection of mir-145 mimics and antagomir-145 20
Immunofluorescence 20
Cell scratch injury 21
MTT cell viability assay 21
Cell proliferation assay 21
Cell motility 22
Transwell migration assay 22
Western blot analysis 23
Quantification of GFAP+ or Iba1+ cells in the injured spinal cord 23
Measurement of the length and number of astrocytic processes 24
3’-UTR luciferase reporter assay 24
Statistical Analysis 25
Results 26
Spatial expression pattern of mir-145 in adult rat spinal cord 27
Expression of mir-145 in distinct spinal cell types 27
Reduced expression of mir-145 in the injured spinal cord 28
Downregulation of mir-145 expression in astrocytes by inflammatory stimuli 28
Regulation of mir-145 expression in astrocytes by p38 MAPK and ERK1/2 signaling pathways 29
Hypertrophy is attenuated in astrocytes with mir-145 overexpression 30
Glial scar suppressed by mir-145 overexpression 30
Regulation of astrocytic dynamics by mir-145 31
GFAP is one of mir-145 targets 32
C-Myc is one validated target of mir-145 34
Mir-212 expression in adult spinal cord 35
SCI-induced downregulation of mir-212 36
Discussion 38
Mir-145 in SCI-associated astrogliosis 39
Mir-145 targets 42
Mir-212 in neural function 43
Inflammation regulation of Mir-145 and mir-212 44
Astrogliosis in tissue repair 44
Astrocytes in brain and spinal cord 45
Potential function of mir-212 in oligodendrocytes 46
References 48
簡歷 95
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