2011-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/682907摘要：水解磷酯酸(lysophosphatidic acid, LPA)是一個酯質媒介物可利用其已知之六個G蛋白質結合受體(LPAR1-6)刺激多種細胞反應。LPA主要由一種分泌型之lysophospholipase D，autotaxin (ATX)所產生。ATX-LPA訊息傳遞軸為胚胎發育及心血管生成之所必需，然其調節機制則不明。利用斑馬魚為模式，我們在先期試驗中發現以嗎&#21833;基(morpholino oligonucleotides, MO)弱化LPA受體3 (lpar3)或atx造成心臟水腫、循環變慢且腹部靜脈欉形成不全。為探究其原因，我們亦發現其心臟管左傾及右環繞之現象也被影響。我們亦將深入探討其機制瞭解LPA訊息如何調控左右不對稱性。同時為通盤瞭解LPA訊息如何調節心臟基因表現，我們將研究其基因轉錄體之變化以尋找調節心臟發育之關鍵因子。最後因微核醣核酸(miRNAs)在調節心臟發育之角色已漸為人知，我們將利用深度定序之方法研究斑馬魚心臟miRNAs，並探討其受到LPA訊息調控之影響。我們將選擇在心臟低或高量表現和受LPA訊息影響之miRNAs及其所調節之基因來探討其在心臟發育之功能。LPA訊息調控對心臟左右不對稱性之影響為全新之發現，同時本計畫利用系統生物學之研究方法將可對LPA如何調控心血管發育之機制有更深層及通盤之瞭解。<br> Abstract: Lysophosphatidic acid (LPA) is a lipid mediator that stimulates a plethora of cellular responses through activation of six known G-protein-coupled receptors (LPAR1-6). LPA is mainly produced by a secreted lysophospholipase D, named autotaxin (ATX). The ATX-LPA signaling axis is essential for embryonic and cardiovascular development, but its regulatory mechanism is unclear. In preliminary trials, we have observed that knockdown of LPA receptor 3 (lpar3) or Atx (atx) by antisense morpholino oligonucleotides (MO) synergistically caused cardiac edema, blood pooling and reduced circulation. In addition, the formation of abdominal venous plexus was also hindered. We will dig in to explore mechanistically detail of how LPA signaling exerts its effects on cardiogenesis. Furthermore, to have a global understanding of LPA signaling on the gene expression, we will investigate the change in transcriptome in the hope to discover key players mediated by LPA for the determination of LR patterning. Lastly, the importance of microRNAs (miRNAs) in regulating cardiogenesis has just been explored. We will thus use deep sequencing to study the miRNAs profile in zebrafish heart and examine its influence by LPA signaling. Candidate miRNAs will selected by their abundance and changes imposed by LPA signaling to determine their roles in cardiogenesis. The regulation of cardiogenesis by LPA-mediated LR asymmetry is a novel finding and the completion of this project will lead to global understanding of both changes in transcriptome and cardiac miRNAs to provide mechanistic explanation of how LPA signaling exerts its effect.水解磷酯酸斑馬魚心臟發育左右不對稱性系統生物學lysophosphatidic acidzebrafishcariogenesisleft-right asymmetrysystem biology