2010-01-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/702021摘要：始基生殖細胞在胚胎發育的初期就開始分化，並隨即依照固定路徑由生成處遷移至性腺發育之性腺脊。雖然學界一向猜測醣胺多醣參與始基生殖細胞遷移之調節，但一直沒有直接的證據可以證明。最近的研究顯示，趨化因子CXCR4、CXCR7以及趨化激素CXCL12乃為引導始基生殖細胞之重要因子，而體外實驗顯示硫酸乙醯肝素醣胺多醣在CXCR4/CXCL12的趨化導引作用中，可能扮演了重要的角色。&#65533;此外，利用神經細胞遷移為模型的研究顯示，CXCR4/CXCR7的活動，乃是由Wnt與Fgf之間的交互作用所調節。在先前的研究當中，我們曾證實硫酸乙醯肝素蛋白聚糖agrin藉由其硫酸乙醯肝素醣胺多醣，與Fgf8共同&#65533;調節視網膜的發育。本計畫欲針對始基生殖細胞之遷移，研究硫酸乙醯肝素蛋白聚糖在其中所扮演的角色。本計畫有以下三項重要目標：（1）調查始基生殖細胞在遷移前、遷移中以及遷移後之基因表現概況，以期對遷移前後的基因調控活動有更全面的了解；（2）轉殖並研究乙醯肝素&#37238;以及硫酸酯&#37238;等與細胞外硫酸乙醯肝素醣胺多醣代謝有關的基因特性，及其在胚胎發育時期之作用；（3）藉由在始基生殖細胞中操控上述基因以及其它由基因表現概況中發現的新基因，了解硫酸乙醯肝素醣胺多醣在始基生殖細胞遷移中所扮演的角色。&#65533;無論是Wnt、Fgf或CXCR4都被認為在不同的腫瘤細胞之轉移中，有著相當重要的作用，此外CXCR4在HIV病毒感染中也有著相當關鍵的作用，我們希望能藉由本計畫之研究，更加深入了解硫酸乙醯肝素醣胺多醣與這些生物分子之間的交互作用機制，以期能在未來為腫瘤轉移或病毒感染提供預防或治療的方法。<br> Abstract: Early in embryonic development, primordial germ cells (PGCs) are specified and migrate from the site of their origin, to where gonads develop, following a specific route. It has long been speculated that proteoglycans play a role in regulating this migration. Recently, CXCR4/CXCL12/CXCR7 signaling has been reported to be the major pathway that directs PGC migration. This signaling pathway has been reported to be involved in various biological activities, including tumor cell metastasis and HIV-1 viral infection. In vitro evidence showed that heparan sulfate (HS) plays a role in regulating CXCR4/CXCL12 signaling. Furthermore, experimental data suggested that CXCR4/CXCR7 is regulated by interactions between Wnt and Fgf signaling pathways in directing PGC cell migration. In previous studies, my work demonstrated that Fgf8 signaling in retina development requires the heparan sulfate proteoglycan (HSPG) agrin. In this research project, the molecular mechanisms involved in PGC migration are proposed to be studied with an emphasis on whether HSPGs are involved in this process. Three specific aims are proposed as follows: (1) to establish a gene expression profile for PGC before, during and after their migration; (2) to clone and characterize genes that are involved in metabolism of extracellular HS glycosaminoglycans (GAGs) including heparanase (HSPE), sulfatase1 (Sulf1), and sulfatase2 (Sulf2); and (3) to further manipulate the genes mentioned above, as well as the genes identified in gene expression profiles in PGC, to elucidate the possible roles of HSPGs in PGC migration. The goal of these studies is to provide novel insight into the molecular mechanisms underlying interactions between HS-GAGs and other molecules such as CXCR4 and CXCL12, and hence provide clues for preventive or therapeutic measures for health issues such as tumor metastasis or HIV infection.硫酸乙醯肝素蛋白聚糖始基生殖細胞趨化因子纖維母細胞生長因子heparan sulfate proteoglycanprimordial germ cellchimokinefibroblast growth factorwnt