探討中風後促進神經再生的功能性與回復機制

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題名:	探討中風後促進神經再生的功能性與回復機制 Targeting of neuroregeneration in vivo to promote functional recovery after stroke
作者:	林冠億 Lin, Guan-Yi
貢獻者:	醫學科學研究所楊志豪
關鍵詞:	中風;神經再生;功能性回復 stroke;neuroregeneration;functional recovery
日期:	2016
上傳時間:	2021-11-11 14:49:27 (UTC+8)
摘要:	腦中風是一種常見且會威脅性命的神經疾病，全球約有兩千五百萬的人口曾罹患腦中風，在美國每年約有十六萬人因腦中風而死亡，在台灣每年約有一萬人因腦中風而死亡。目前臨床上卻僅有rt-PA血栓溶解劑用來治療腦中風，其可溶解血栓使腦部恢復氧氣及血流供應，卻也大幅增加腦部和其他組織出血的風險。因此，目前迫切需要開發更有效的策略來治療因為缺氧所導致的腦神經損傷。許多研究證實在成人腦部中仍有神經幹細胞的存在，並可在大腦成熟後持續產生新的神經細胞。雖然陸續有研究顯示，在腦部受到缺氧損傷後會促進神經再生的能力，但目前大多數中風引起的神經受損仍無法有效復原。因此我們假設腦部在受到缺血缺氧刺激後造成局部環境的改變可能會阻礙新生神經細胞的成熟。為了回答這個問題，我們利用反轉錄病毒載體標定活體中的新生神經細胞，藉此追蹤新生神經細胞的成熟過程。我們發現，腦部在受到缺血缺氧刺激後會延緩新生神經細胞的成熟過程，可從反轉錄病毒標定後發現，在第14天、21天與28天的樹突總長度與分支數有減少的情形，同時，在中風之後會導致新生神經細胞的突觸在連結神經網路時會有明顯的受損。接著在中風後去分析不同時期神經再生的情形，在缺血缺氧第7天與第14天時，HDAC6會易位到細胞核導致α-tubulin過度的乙醯化 (顯示微管為過度穩定的狀態)。此外，直接在老鼠投予中HDAC6的抑制劑Tubastatin A可以產生和中風干擾神經再生類似的影響而導致樹突與突觸遲緩生長的情形。我們目前的研究顯示，在缺血缺氧腦傷的環境中確實會影響成年新生神經細胞成熟的過程，因此可藉由藥物來促進成年神經細胞再生或是用HDAC6作為治療的標靶，作為將來臨床上中風可能的治療方針。 Stroke is one of the leading life-threatening neuropathology. Around 2.5 billion people worldwide have suffered from episodes of stroke throughout their life. Among these figures, one hundred sixty thousand people in the United States and more than ten thousand people died of stroke each year in Taiwan. However, only one drug: rt-PA (recombinant tissue plasminogen activator) which can dissolve the thrombus has been approved for the treatment of ischemic stroke. Therefore, there is an urgent need to develop innovative and efficient therapeutic strategies toward promoting functional recovery after hypoxia challenge. Numerous studies have proven the presence of neural stem cells in the mature brain which can contribute to adult neurogenesis continuously throughout the adulthood. Although accumulating evidence indicated that increase in capability of neurogenesis after hypoxic insults, neuronal damage induced by stroke does not recovered efficiently in most of the cases. We hypothesized that changes in microenvironment or cellular properties after hypoxic challenge may impede the functional maturation of adult newly regenerated neurons. To answer this question, we applied an in vivo retroviral based labeling approach to trace the maturation process of adult newly regenerating neurons. As we found, there is a significant slowdown of the maturation process for these newly regenerated neurons after hypoxic challenge. As reflected by reduction in total dendritic length and number of branches at 14-, 21-, and 28-days after retroviral labeling. Meanwhile, the formation of synaptic contacts with the existing circuitry is also significant impaired for the regenerated neurons after stroke. Subsequent biochemical analyses on these regenerated neurons at different stages after stroke revealed an aberrant nuclear translocation of HDAC6 which leads to the hyper-acetylation of α-tubulin (an indication for over-stabilization of microtubules) at 7 and 14 days after hypoxic challenge. Furthermore, a mimicry experiment with HDAC6 inhibitor-Tubastatin A, phenocopied the stroke induced retardation of dendritic elaboration and synaptic formation in vivo. Our current study provides the direct evidence showing that hypoxic challenge may impede the functional maturation of adult newly regenerated neurons. Pharmacological treatment aims on boosting of adult neuroregeneration or targeting of HDAC6 may be a promising therapeutic direction toward the patients with stroke in clinic.
描述:	碩士指導教授：楊志豪
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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