2009-03-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/682717摘要：Lysophosphatidic acid (LPA)為水解磷酸脂的一種，藉由與其細胞表面特定的Edg族受器結合，以調節各項細胞生理活性反應。LPA被發現能夠刺激細胞的增生、移行、蛋白酵素的活化，以及調節內皮細胞多種發炎反應相關基因的表現，顯示LPA是調控血管生理之重要因子。於本實驗室初步的研究成果中發現， LPA能夠刺激人類臍靜脈內皮細胞淋巴血管新生因子VEGF-C的表現，並促進人類內皮細胞形成管狀結構及表達淋巴血管之特殊分子標記。此外，LPA接受器之去活性會造成斑馬魚之淋巴系統形成受到阻礙。然而，有關LPA於調節淋巴血管形成以及淋巴血管新生作用的角色仍待釐清。本計劃擬分為四部分進行研究： 在計畫的第一部份，我們將釐清LPA刺激哺乳類內皮細胞中VEGF-C表現之詳細訊息傳遞機制。 在計畫的第二部分，我們將深入探討LPA刺激哺乳類內皮細胞之淋巴管形成是經由哪些訊息傳遞機制所調控。 於計畫的第三部分，我們將更進一步探討LPA1受器於調節哺乳類與魚類體內淋巴血管新生作用之差異性。 於計畫的第四部分，我們將探討LPA於調控癌症細胞參與淋巴血管新生作用之角色。 <br> Abstract: Lysophosphatidic acid (LPA) is a small-molecular-weight lipid growth factor which binds to G-protein-coupled receptors and activates a variety of physiological functions. Previous studies published in our laboratory demonstrated that LPA enhances cell proliferation, migration, activation of proteases, and expression of inflammatory-related genes in human endothelial cells. These results suggested that LPA plays important roles in regulating endothelial cell functions. Our preliminary results demonstrated that LPA regulates the expression of VEGF-C, a lymphangiogenic factors, in human umbilical vein endothelial cells (HUVECs). In addition, LPA also enhance endothelial cell tube formation and the expression of lymphatic markers in these tubes. Furthermore, knockdown of LPA1 receptor resulted in lymphatic defect in zebrafish. These results suggested that LPA is an important regulator of lymphatic vessel formation. However, the role of LPA on regulating lymphangiogenesis has not been well studied. In this proposal, we attempted to investigate: 1. the detailed signaling mechanism of LPA-induced VEGF-C expression in human endothelial cells; 2. the detailed signaling mechanism of LPA-induced lymphatic vessel formation in human endothelial cell; 3. the role of LPA receptors in regulating lymphatic vessel formation in mice and in zebrafish; 4. the roles of LPA on cancer cells in regulating lymphangiogenesis. This study provides some basic information that LPA might be a novel target for therapeutics against lymphangiogenesis and tumor metastasis.水解磷酸脂淋巴管生成C-型血管生成因子lysophospholipid lymphangiogenesis VEGF-C