創傷型腦損傷是一種高度複雜的病症，它導致許多青少年與成人的死亡與傷殘。創傷型腦損傷包含了許多效應，像是中樞神經系統的發炎反應、血腦屏障的受損、腦內氧化壓力的上升等生理上的變化，而這些效應會進一步造成中樞神經的退化、神經元的受損、凋亡與自體吞噬作用等續發型腦損傷。先前的研究已知TGF-β訊息傳遞的路徑對於神經元維持其完整性有其重要性。在另一方面，TGIF (TG-interacting factor)已知為TGF-β訊息傳遞的抑制分子，然而，TGIF在創傷型腦損傷的發展過程中所扮演的角色至今仍尚未明瞭。因此，我們將研究TGIF在創傷型腦損傷大鼠模式中所扮演的角色。在我們所得到的結果中，我們發現TGIF在大鼠腦部受創側的皮層會有過度表現的情形，而且大部分都表現在活化的微小膠質細胞內。因此我們進一步利用與發炎相關的細胞激素IFN-γ以及TNF-α刺激微小膠質細胞BV-2活化並觀察TGIF表現的情形。然而，在BV-2細胞中，我們只觀察到IFN-γ可以促進TGIF表現量上升。接著，我們進一步抑制BV-2細胞中TGIF的表現，結果發現細胞在IFN-γ刺激後所產生的活性氧分子總量會有明顯的下降，且BV-2細胞外觀也呈現較不活化的型態，顯示出TGIF可能有促進微小膠質細胞發炎反應的作用。最後，我們利用腦內注射的方式來減少大鼠腦創傷病灶處TGIF的表現，並且發現這樣的方式確實能夠降低創傷型腦損傷大鼠大腦梗塞壞死的情形、減少病灶處微小膠細胞增生的現象，並且使後肢運動能力在創傷後得到較好的回復情形。總結來說，我們認為TGIF在創傷型腦損傷後微小膠質細胞的活化扮演著重要的角色，在未來有希望可以成為減緩創傷後發續發型腦損傷的一個標的。

Traumatic brain injury (TBI), the leading cause of death and disability in young children and adults, is a highly complex disorder, including neuroinflammation, blood-brain barrier disruption, raise of oxidative stress, and other physiological alterations. Collectively, these effects result in the secondary damage, including neurodegeneration, apoptosis or autophagy of neurons, as well as neurological impairment. TG-interacting factor (TGIF) is a transcriptional co-repressor to inhibit TGF-β signaling pathway which plays a role of protector to maintain neuronal integrity. However, the role of TGIF in TBI is still unclear. Hence, we aimed to investigate the role of TGIF in a TBI rat model. In our study, we found that TGIF was overexpressed and mainly co-localized in active microglia at the peri-contusional cortex of rats underwent TBI operation. Therefore, we suggested that TGIF might be associated with microglia activation after TBI. To prove the hypothesis, two TBI-related pro-inflammatory cytokines, IFN-γ and TNF-α, were used to treat mouse microglial cell line BV-2. We found that only IFN-γ induced TGIF expression in a time- and dose-dependent manner. IFN-γ induced reactive oxygen species (ROS) production and BV-2 cells active morphology were decreased by knockdown of TGIF expression. We suggested that TGIF might promote the inflammatory responses in microglia. Finally, we used intracerebral injection to knockdown TGIF in the lesion of trauma. This method could significantly attenuate the infarction volumes, reduced microgliosis and recovered the limb motor function of the rats. Taken together, we suggest that TGIF plays an important role in TBI-induced microglia activation, and it might be a promising target to attenuate the secondary damage of TBI in the future.

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