Epac1 為許多病症的調控蛋白，而高度的表現Epac蛋白會引起癌症、糖 尿病、中樞神經失調以及阿茲海默症等疾病。雖然已有文獻指出，cAMP 可促進 神經軸突的生長；且Epac在結合接受體integrin後，則可活化經由integrin所調控 之內皮幹細胞(EPCs)生成路徑；但由Epac刺激其神經軸突再生之分子相關機制， 則有待進一步的驗證。再者，於實驗動物模式中發現，將Epac1之促進劑 8-pCPT-cAMP 注入受損的神經組織後，能有效促進腦中風區域之內皮幹細胞 (EPCs)再生以及腦血管新生。實驗結果發現，缺血/缺氧後，組織中之Epac1蛋白 會被大量活化；猜測與組織受損後，細胞的修復機制有關。因此，於本計劃中我 們將深入探討，在已知的缺氧誘導機制下，Epac1是否會透過HIF-1α調節，促進 Epac1-Rap1訊息傳遞路徑，增加腦中風後之神經修復機制。由於本實驗室近期更 發現，G-CSF在有氧的情況下，能高度誘導造血幹細胞中HIF-1α蛋白之表現量； 所以我們將近一步發展G-CSF以及Epac1促進劑8-pCPT-cAMP之雙重療法，並觀 察其對於腦中風後神經可塑性的促進作用，是否有加乘的效果。 Epac1 is related to certain diseases such as cancer, diabetes and central nervous system disorders, including Alzheimer’s disease. Although the signaling pathways mediated by Epac1 to promote axon regeneration are poorly understood, previous studies have indicated that cAMP could enhance axonal growth. Epac1 could activate integrin activity and regulates integrin-mediated EPCs homing. In addition, intravenous injection of pre-stimulated EPCs by specific Epac1 activator (8-pCPT-cAMP) into the ischemic hindlimb model could enhance the homing the EPCs to the ischemic region and promote the angiogenesis. The contribution of tissue hypoxia as a stimulus for the induction of Epac1 is not known. Although the pathophysiological change of Epac1 expression has not been characterized, we have found that the Epac1 could be upregulated by the hypoxia/ischemic condition. This protein upregulation might be related to lesion-induced cellular adaptations. Therefore, in this study, we intended to disclose the molecular mechanism in the expression regulation of Epac1 under hypoxia-induced HIF-1α activation. Because recent evidence have also demonstrated that G-CSF could induce high level of stable HIF-1α under normoxic condition in hematopoietic stem cells, we also would develop the additive therapeutic approach using specific Epac1 activator (8-pCPT-cAMP) and G-CSF in the stroke model. PDF
