2018-08-012024-05-15https://scholars.lib.ntu.edu.tw/handle/123456789/665415摘要：缺血性腦中風的致病率及死亡率在全世界都是排名前幾名的疾病，且造成極大的醫療及照顧 上的負擔。在近期的研究中發現紅血球生成素（erythropoietin, EPO)除了具有促紅血球生成 的功能外，在缺血性腦中風的情況下具有神經保護功能。然而，因為血腦障壁（blood-brain barrier)阻隔EPO進入腦組織内，必須給予高劑量的EPO才能達到神經保護作用，也因此 容易造成造血相關不良反發生。一些擬紅血球性胜肽（EPO mimetic peptides)，僅保有神經 保護的作用，但沒有促紅血球生成的功能，是一個相當有潛力的神經保護胜肽。如能有效的 攜帶此類胜肽通過BBB，則可以提高治療的成效及減少藥品花費。透過非侵入性的方式將 藥品有效且安全的遞送至中樞神經系統，是目前中樞神經藥品遞送系統的發展目標。本研究 室發展出的穿膜胜肽HBHAc，由25個胺基酸所組成，過去我們已經利用HBHAc作為蛋白 質藥品（arginine deiminase, ADI)細胞内遞送之載體，克服ADI使用後的抗藥性。本研究， 藉由HBHAc具有的穿胞作用（transcytosis)，我們提出利用HBHAc-EPO-derived peptide來 達到有效穿透BBB能力的新遞送模式，有效的讓EPO-derived peptide發揮神經保護的功能。 三年計劃的目標如下：1.建立一個良好的體外神經細胞模型評估HBHAc-EPO-derived peptide的穿透BBB能力及神經保護作用。2.利用基因合成單一均質的融合胜肽。3.評估 HBHAc-EPO-derived peptide於疾病小鼠内的治療效果及藥動學。透過這個新的藥品遞送系 統使HBHAc-EPO-derived peptide有效的遞送至中樞神經系統，進而達到有效的神經保護效 果，且降低全身性的不良反應。<br> Abstract: Ischemic stroke is a leading death disease with a heavy disease burden globally. In recently research, erythropoietin (EPO) not only has the erythropoiesis activity but also the neuronal protection in the condition of ischemic stroke. However, the extremely high dose EPO is required to elicit the neuronal protection due to the blood brain barrier. Some EPO mimetic peptides have been designed with only neuronal protective activity. If there is an efficient delivery of peptides to central nervous system (CNS), it would optimize the treatment of ischemic stroke. In our previous studies, HBHAc has been used as an intracellular delivery of a protein drug (arginine deiminase, ADI), overcoming the ADI-resistance cancer cells. In this study, we would like to apply HBHAc with its transcytosis ability in CNS peptide delivery of HBHAc-EPO-derived peptide. In this 3-year project, our goals are 1. Evaluate the ability of HBHAc and EPO-derived peptides in crossing BBB and neuroprotection. 2. Develop homogenous HBHAc-EPO-derived peptides for the delivery system. 3. Demonstrate the efficacy and disposition of the optimized HBHAc-EPO derived peptide in vivo. After this comprehensive study, HBHAc-EPO-derived peptide can be delivered efficiently into CNS and apart from hematopoietic adverse effects by the novely designed deliver system, and subsequently increase the efficacy in neuroprotective activity and minimize the systemic adverse effects.神經保護紅血球生成素中樞神經遞送穿胞胜肽neuroprotectionerythropoietinCNS deliverycell-penetrating peptide