2012-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660696摘要：吾人最近發現血管周邊細胞(pericyte)是造成腎臟纖維化之纖維母細胞的主要來源，而過去在眼睛與大腦的發育過程中已證實perictye是維持血管新生與血管穩定的重要細胞。因此吾人希望進一步研究腎臟在受到損傷時如何透過血管內皮細胞與pericyte的交互對話而刺激pericyte增生、移位、與分化成肌肉纖維母細胞，而過度增加的纖維母細胞又如何反過來造成血管內皮細胞凋亡與血管不穩定、稀少化。腎臟或其他器官在受到傷害之後造成微血管稀少化會進一步導致器官的缺氧、慢性發炎，終至器官纖維化萎縮與功能喪失。因此防止微血管稀少化與器官缺氧的治療就越顯需要。由血管新生的研究已知血管內皮細胞可以分泌血小板衍生生長因子(PDGF)以刺激pericyte的同源受體(PDGFRβ)，然而在腎臟的纖維化中，PDGF卻扮演了促進的重要角色。當血管內皮細胞大量表現PDGF時，反而會促進血管稀少化、降低血管密度，這意味著過度增生與擴張的pericytes/纖維母細胞可能反過來分泌促進血管內皮細胞凋亡的因子或減少了維持血管內皮細胞穩定的因子。雖然在發育過程中pericyte可以經由分泌血管內皮細胞生長因子(VEGF)，而且從腎小球足細胞分泌的VEGF是腎小球微血管發育所必需，然而因為VEGF的受體包括VEGFR1 (Flt1)與VEGFR2 (Flk1)具有促進血管內皮細胞增生與巨嗜細胞活化的不同功能，且VEGF的因為轉錄splicing的不同而有各種不同的isoform，這些因素使得VEGF-VEGFR的作用訊息變成相當複雜，不僅僅是配合基與受體的交互作用而已。因此吾人第一年將分別利用VEGFR2與PDGFRβ的細胞外domain來進行專一性的拮抗以研究活化VEGFR或PDGFR的訊息對於pericyte增生、移位、與分化的影響。第二年將研究為何在漸進性的腎臟疾病中VEGF isoform會從VEGF164為主轉變成以VEGF120及VEGF188為主，而這種轉變對於血管稀少化及腎臟纖維化的角色何在。第三年將探討漸進性腎臟疾病中日益增加的angiopoietin-2的來源與其在血管稀少化中扮演的角色。經由這些研究，吾人相信必能發展出防止腎臟微血管稀少化與腎臟缺氧與纖維化的新治療。<br> Abstract: Prompted by recent identification that pericytes in the kidney are the source of scar formingmyofibroblasts and previous studies in the eye and brain that identified pericytes as pivotal cells indevelopmental angiogenesis and vascular stabilization, we wish to determine whetherinjury-stimulated pericyte-endothelial cross-talk leads not only to migration of pericytes fromcapillaries and differentiation into myofibroblasts but also destabilization of capillaries in thekidney. Microvascular rarefaction following injury in the kidney and other organs is increasinglyimplicated in organ ischemia, chronic inflammation and progressive loss of organ function.Therefore strategies to prevent microvascular rarefaction are highly desirable. Regulatedplatelet-derived growth factor (PDGF) signaling from endothelial cells to pericyte PDGF receptor β(PDGFRβ) has been shown to be vital in vascular stabilization in sprouting angiogenesis, andPDGFs have been implicated in fibrogenesis. PDGF-overexpression in endothelial cells however,paradoxically promotes vascular rarefaction decrease the vascular density, suggesting thatproapoptotic factors are released from or survival factors are downregulated in expandedpericytes/fibroblasts. Although vascular endothelial growth factor (VEGF) signaling from pericytesto endothelial cells has been implicated in developmental angiogenesis, and more recently VEGFsignaling from the specialized pericytes of the kidney glomerulus known as podocytes has beenshown to be crucial for vascular stabilization, the presence of both VEGF receptor 1 (VEGFR1, Flt1)and receptor 2 (VEGFR2, Flk1) on endothelial cells and regulated expression of three distinctVEGF genes and multiple transcription splice variants renders VEGF signaling more complicatedthan simple binary ligand-receptor interactions. In this 3-year project we will first delineate thesignaling from injury-stimulated endothelial cells to neighboring pericytes by selective targeting theVEGFR and PDGFRβ signaling. We will next study the role of VEGF isoform switch inprogressive kidney fibrosis and vascular rarefaction. We will finally study the role of increasedangiopoietin 2 in the endothelial apoptosis and vascular rarefaction in progressive kidney disease.We hope to develop novel therapies to prevent microvascular rarefaction and kidney fibrosisthrough targeting angiotrophic growth factors in progressive kidney disease.