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研究生：	黃泰淳 Huang, Tai-Chun
論文名稱：	缺氧誘導因子1α在頭部外傷後調節神經新生所扮演之角色 The Roles of Hypoxia-Inducible Factor 1α (HIF-1α) in the Traumatic Brain Injury-Induced Neurogenesis
指導教授：	呂國棟 Lu, Kwok-Tung 楊奕玲 Yang, Yi-Ling
學位類別：	博士 Doctor
系所名稱：	生命科學系 Department of Life Science
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	148
中文關鍵詞：	頭部外傷、內皮血管生長因子、缺氧誘導因子、絲裂原活化蛋白激酶、微小型片段RNA-210 、雙特異性去磷酸酶6
英文關鍵詞：	Trauma brain injury, Vascular endothelial growth factor, Hypoxia inducible factors, Mitogen activated protein kinase, miR-210, Dual-specificity phosphatase 6
DOI URL：	http://doi.org/10.6345/NTNU201900845
論文種類：	學術論文
相關次數：	點閱：130 下載：0
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頭部外傷 (traumatic brain injury, TBI) 是全世界青壯年人口中¬，盛行率和死亡率雙高的意外事故之一。因頭部外傷主要發生在最具有生產力階段的青壯年人口，在頭部外傷病患中約有25% 會造成終身性殘疾並須長期性的照護，因而造成社會或經濟的損失。因此，相關致病機轉和醫療策略的研發極具重要性。我們先前的研究已經證明血管內皮生長因子（vascular endothelial growth factor, VEGF）調節TBI所引發之神經新生的現象(TBI-induced neurogenesis)是經由活化第二型的VEGF受體 (VEGFR2) 和活化絲裂原活化蛋白激酶 (mitogen activated protein kinase, MAPK) 訊息傳導路徑。前人研究指出缺氧誘導因子（hypoxia inducible factor, HIFs）在正常狀態細胞中含量較為稀少，但在病理狀態下，如缺血(ischemia) 或缺氧 (hypoxia) 時表現會被誘導大量增加。細胞中的HIFs扮演轉錄因子的角色，會進而誘導多種類型的下游基因之表現，特別是與負責血管增生(angiogenesis)、厭氧反應 (anaerobic)、血管舒張 (vasodilation)、紅血球細胞生成(erythropoiesis)、神經新生 (neurogenesis)。本研究的主要目的為探討HIF-1α在TBI誘導海馬迴內神經新生的角色。
第一部份的研究結果發現TBI誘導後可以引起VEGF表現和海馬迴內的神經新生。此外，給予HIF-1α的反義股 (antisense) 或專一的抑制劑2ME2 (2-methoxyestradiol)成功地阻斷了TBI誘導海馬迴神經新生。TBI的誘導下，與HIF-1α降解有關兩個主要酵素中的脯胺醯基羥化酶 (prolyl hydroxylase, PHD)的表現減少，而低氧誘導因子-1 抑制因子 (factor-inhibiting HIF, FIH) 的表現則無改變，我們推測PHD的減少是促使TBI後海馬迴內的HIF-1α蛋白量增加的主要原因。此外，我們也排除了其他HIF亞型，如HIF-2α和HIF-3α參與此機制的可能性。後續實驗中也證明了HIF-1α可以結合VEGF的啟動子以調控其表現。總結第一部分的實驗結果，我們證明是HIF-1α而非HIF-2α和HIF-3α為激活VEGF在TBI後大量表現的轉錄因子，以及海馬迴中TBI誘導神經新生的主要因子。故在第二份實驗中，我們專注於探討影響TBI後HIF-1α表現量增加後的下游機制，特別是微小型片段RNA（microRNA, miR）是否在過程中扮演重要的角色。
第二部分的實驗證明了miR-210在缺氧後參與了調節海馬迴中的神經新生。TBI後海馬迴中miR-210表現量迅速提升，約在4小時達到峰值，並在8小時內回復到基礎值。給予miR-210 shRNA不僅可有效的抑制miR-210的表現，同時也減少了TBI所引起的神經新生。此外，西方墨點法的結果顯示TBI誘導後MAPK 訊息傳遞路徑中，三個主要的蛋白質RAF-MEK-ERK的磷酸化均呈現增加，同樣的這些蛋白質的磷酸化情形，在經過miR-210 shRNA預處理後均恢復到正常範圍內。進一步探討TBI造成MAPK磷酸化改變的原因，發現海馬迴內的雙特異性去磷酸酶6 (dual specificity phosphatase 6, DUSP6)，還造成RAF-MEK-ERK訊息傳遞去磷酸化的主要磷酸酶，其表現量在TBI誘導後大量減少，我們推論miR-210可能會鍵結DUSP6的mRNA上進而造成其表現量下降。為了驗證上述假設，我們使用慢病毒紅螢光報告系統 (lentivirus report system)，該系統可藉由紅色螢光蛋白 (DsRed) 的表現來偵測miR-210是否會結合DUSP6 mRNA。結果發現DeRed蛋白質的表現在TBI前處理LV-DUSP6組中顯著地減少，證明了miR-210確實具有結合DUSP6 mRNA的能力，進而直接調控DUSP6的轉譯作用，使得在TBI後DUSP6減少，導致MAPK的磷酸化增加，進而促進神經新生的產生。
綜合以上各項結果，我們認為miR-210可當作一個重要的生物指標，可用以探測TBI所引起的腦損傷；而TBI所造成的HIF-1α表現量增加，可進一步促進miR-210的產生，miR-210 可鍵結到DUSP6的mRNA上以減少其表現，進而導致MAPK的磷酸化增加，最終提升了TBI後海馬迴的神經新生。因此藉由增強或延長TBI誘導後HIF-1α的表現，應可作為研發針對TBI傷害的新型治療策略或藥物的重要標的。

Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity and mortality in youths all over the world. It affects young adults mainly in their most productive stage of life and produces long-lasting disability in 25% of cases, causing an enormous social and economical lost. Our previous studies have evidenced that vascular endothelial growth factor (VEGF) mediated the TBI-induced neurogenesis via VEGF receptor 2 and mitogen activated protein kinase (MAPK) pathway. Hypoxia inducible factors (HIFs) are normally limitedly produced in cells but remarkably up-regulated during some pathological events such as ischemia and hypoxia. HIFs serve as transcription factors and induce the expression of several classes of genes which are related to angiogenesis, anaerobic oxidation, vasodilation, erythropoiesis, and neurogenesis. The present study is aimed to study the possible involvement of HIF-1α in the TBI-induced neurogenesis in hippocampus.
In part-I experiments, we found that HIF-1α is responsible for the TBI-induced VEGF expression and hippocampal neurogenesis. In addition, either HIF-1α antisense or specific inhibitor 2-methoxyestradiol (2ME2) administration could successfully block the TBI-induced hippocampal neurogenesis. The reduced expression of HIF-prolyl hydroxylases (PHD) but not the factor-inhibiting HIF (FIH) was accounted for the increasing of hippocampal HIF-1α after TBI. Furthermore, we also excluded the possible involvement of other HIF isoforms, such as HIF-2α and HIF-3α. We proved that HIF-1α could bind to the VEGF promoter and regulate its expression. In summary of the part-I experiments, we concluded that HIF-1α is critical to TBI-induced neurogenesis via activating VEGF gene expression.
In the part-II experiment, some microRNAs (miRs), such as miR-210, were proven to participate in the regulation of neurogenesis after hypoxia. miR-210 is the most consistently and robustly induced miRs under hypoxia. We focused on investigating the involvement of miRs in the increasing of hippocampal HIF-1α and neurogenesis after TBI. The elevated miR-210 expression reached the peak and returned to normal level at around 4 h and 8 h after TBI, respectively. Administration of miR-210 shRNA not only effectively suppressed the overexpression of miR-210, but also attenuated TBI-induced neurogenesis. The western blot results showed the phosphorylation of RAF-MEK-ERK was increased by TBI and the phosphorylation levels of those proteins were returned was restored to the normal range by pre-treated with miR-210 shRNA. Furthermore, the expression of the hippocampal dual-specificity phosphatase 6 (DUSP6), an essential phosphatase of regulating the dephosphorylation of the RAF-MEK-ERK signaling cascade, was reduced after TBI. These results were further verified by using a lentivirus driven reporter system (with a red fluorescence protein, DsRed). We found that the expression of DsRed protein was significantly decreased by pre-treated with LV-DUSP6 after TBI treatment. This result evidenced the miR-210 might be able to regulate the translation of DUSP6 in a direct manner. Conclusively, the present study investigated that miR-210 could serve as an important biomarker for the prognosis of TBI-induced brain damage.
Conclusively, the present study demonstrated the TBI-induced HIF-1α expression is critical to the generation of miR-210, which in turn will in term to reduce the expression of DUSP6 expression and results in the activation MAPK signal cascade and neurogenesis. Therefore, we suggest that either enhance or prolong the TBI-induced HIF-1α expression might be an effective and promising target for the development of novel therapeutic strategies on the neuroprotection and neural regeneration of the TBI.

Abstract    i
中文摘要    ii

Introduction    1
1.1 Traumatic brain injury    1
1.1.1 Classiﬁcation of traumatic brain injury    2
1.1.2 Pathophysiology of traumatic brain injury    3
1.2 Hypoxia-inducible factor (HIF)    4
1.3 Adult neurogenesis    8
1.4 Vascular endothelial growth factor (VEGF)    10
1.5 The mechanism and function of microRNAs    13
1.6 miR-210 and HIF-1α are coordinately regulated    14
1.7 Mitogen-activated protein kinase (MAPK)    15
1.7.1 The role of the mitogen-activated protein kinase pathway in neural development    16
1.8 Dual-specificity phosphatase (DUSP or MKP)    17
1.8.1 The dual-specificity MKP gene family    18
1.8.2 The introduction of MKP-1/MKP-2    19
1.8.3 The introduction of MKP-3    21
Hypothesis and research aims    24
Materials and Methods    25
2.1 Animals    27
2.2 Traumatic brain injury model and tissue preparation    27
2.3 Administration of oligonucleotides and drugs    27
2.4 Total RNA extraction and reverse transcriptase polymerase chain reaction (RT-PCR)    28
2.5 Protein extraction and quantification assay    32
2.6 Western blotting assay    33
2.7 Chromatin immunoprecipitation (ChIP)    35
2.8 Real-time polymerase chain reaction (qPCR)    38
2.9 Immunofluorescence    38
2.10 MicroRNA expression assay    41
2.11 Plasmid construct    42
2.11.1 The reporter plasmid construct for micro-RNA interaction with target gene    42
2.11.2 Competent cell transformation    43
2.11.3 Transformation of stbl3 competent cells with lentivirus plasmid    43
2.11.4 The preparation of plasmid    44
2.11.5 Plasmid construction for micro-RNA was binding the region of specific and shRNA procedure    45
2.11.6 The restriction enzyme and T4 ligase    48
2.12 The animal hippocampus infected by the lentivirus    50
2.13 The construction of miR-210 shRNA.    50
2.14 Verifying the efficiency of the lentivirus-mediated hippocampal DsRed protein expression of the TurboRFP gene on the control plasmid PLKO-TRC020.    54
2.15 Statistical analysis    55
Results    56
3.1.1 The hippocampal hypoxia inducible factor 1 alpha   and vascular endothelial growth factor expression were upregulated in the adult rat after TBI.    56
3.1.2 Administration of HIF-1α antisense significantly decreased the TBI-induced HIF-1α and VEGF expression in hippocampus.    57
3.1.3 The possible involvement of other HIF proteins in the TBI-associated hippocampal VEGF upregulation was excluded.    58
3.1.4 Administration of the HIF-1α inhibitor 2-methoxyestradiol significantly attenuated TBI-induced hippocampal HIF-1α and VEGF expression.    59
3.1.5 Administration of 2ME2 inhibited TBI-induced neurogenesis in the hippocampus.    60
3.1.6. The hippocampal oxygen-sensing prolyl hydroxylase domain enzyme expression was attenuated in the TBI animals    60
3.1.7 Chromatin immunoprecipitation (ChIP) confirmed the involvement of HIF-1α in the promoter activation of VEGF after TBI.    61
3.2.1 The expression of microRNA-210 was increased in the hippocampus of TBI-induced adult rats.    62
3.2.2    Binding of HIF-1 on the promoter region of microRNA-210 by ChIP.    63
3.2.3 Lentivirus-mediated expression of miR-210 shRNA significantly suppressed the TBI-induced expression of miR-210 in hippocampus.    63
3.2.4 Lentivirus-mediated expression of miR-210 shRNA significantly attenuated TBI-induced neurogenesis in the dentate gyrus of the hippocampus.    64
3.2.5 The hippocampal RAF/MEK/ERK signaling pathway was attenuated after the suppression of miR-210 by miR-210 shRNA.    65
3.2.6 The TBI-associated downregulation of dual specificity phosphatases 6 could be effectively restored by miR-210 shRNA expression.    67
3.2.7 The interaction of miR-210 and dual specificity phosphatases 6 was evaluated using a lentiviral reporter red fluorescence protein construct.    68
Discussion    71
Part I    71
Part II    80
Figures & Legends    91
Figure 1    91
Figure 2    92
Figure 3    93
Figure 4    94
Figure 5    96
Figure 6    97
Figure 7    98
Figure 8    100
Figure 9    101
Figure 10    102
Figure 11    104
Figure 12    105
Figure 13    106
Figure 14    107
Figure 15    109
Figure 16    110
Figure 17    112
Figure 18    113
Figure 19    114
Figure 20    116
Figure 21    117
References    118
Abbreviations    136
Index    138
Gel electrophoresis buffer    138
Western blotting buffer    139
Chromatin immunoprecipitation (ChIP)    143
miRNA expression assay    146
                                

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