轉錄因子誘餌及含轉錄因子誘餌之醫藥組成物及其製法與用途TRANSCRIPTION FACTOR DECOYS AND USE THEREOF

專利類型

發明

專利國別 (專利申請國家)

美國

專利申請案號

12/626,969

專利證號

US 8,153,607 B2

專利獲證名稱

轉錄因子誘餌及含轉錄因子誘餌之醫藥組成物及其製法與用途TRANSCRIPTION FACTOR DECOYS AND USE THEREOF

專利所屬機關 (申請機關)

國立中正大學

獲證日期

2012/04/10

技術說明

嚴重敗血症患者呈現全身性發炎、促凝血素質特異體質(prothrombotic diathesis)和纖維蛋白溶解失調，雖然研究指出活性蛋白質 C (Activated protein C；APC)可抑制血栓形成和阻止多重器官衰竭產生，使敗血症死亡率由30.8%下降至24.7%，至於APC如何降低死亡率的機制仍然不完全清楚。我們由文獻分析APC所影響基因中表現量比對照組高兩倍以上且含P300/CBP DNA結合序列的基因共13個，但都缺乏TCF DNA結合序列，因此假設APC可藉由降低細胞核P300/CBP的可利用量減低Wnt/beta-catenin相關之訊號傳遞最後提升受內毒素感染之內皮細胞存活率。實驗設計TR3 orphan調節區內和P300結合序列之基因和cyclin D1及fra1基因調節區之TCF的鍵結序列之為誘捕DNA 用來降低Wnt/beta-catenin相關之訊號傳遞。結果顯示TCF的誘捕DNA對於降低內毒素所造成之內皮細胞死亡之效果優於P300的誘捕DNA及APC。 From the microarray data of Riewald el al., we found that the number of the genes of the activated protein C (APC)-treated endothelial cells with mRNA expression over 2 times of their original is 13. None of the genes contains a TCF binding site. Therefore, we hypothesized that APC may increase the survival rate of the LPS-activated ECs via reducing the Wnt/beta-catenin signaling. We designed two DNA decoys that are derived from P300 binding sequences in the DNA regulatory regions of TR3 orphan receptor and TCF-4 binding sequences of cyclin D1 or fra1 to reduce Wnt/beta-catenin signaling. Our results showed that the Tcf DNA decoy had a greater effect than the P300 DNA decoy and APC on reversing the LPS-induced cell death.

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