PECAM-1 and Retinopathy of Prematurity

描述：血管生成是胚胎循环系统正常发育所必需的，也是许多眼科疾病进展的重要步骤，包括早产儿视网膜病变(ROP)。因此，了解内皮细胞的正常调节系统如何控制血管生成具有重要的临床意义。血小板内皮细胞黏附分子-1(PECAM-1)是血管生成的重要调节因子。我们已经证明，PECAM-1的多种异构体以发育调节的方式在不同组织的血管床中表达。这些异构体能够不同地激活细胞内信号通路，这表明这些异构体在血管发育和血管生成过程中发挥着特定的作用。然而，PECAM-1及其异构体在这些过程中所起的生理作用还有待进一步研究。本研究的主要目的是阐明PECAM-1及其异构体在视网膜血管发育和血管生成中的生理作用，以及在调节视网膜EC黏附和迁移特性中的作用，并阐明其内皮表达受PECAM-1差异调控的基因的功能。具体地说，我们将展示PECAM-1在视网膜血管形成和新生血管形成中的作用，并确定在缺乏PECAM-1的情况下这些过程是如何受到影响的。我们将确定PECAM-1亚型在视网膜血管发育和新生血管形成过程中以及在视网膜内皮细胞(EC)中的表达模式。我们将评估PECAM-1亚型在调节EC黏附和迁移中的具体作用。为了进一步阐明PECAM-1‘S的作用机制，我们将鉴定和进行Enoglin和结缔组织生长因子等基因的功能研究，这些基因的内皮特异性表达受到PECAM-1缺失的差异影响。这些研究将深入了解PECAM-1在视网膜血管发育和血管生成中的生理作用，以及在调节EC黏附和迁移中的作用。这一知识将有助于开发具有新生血管成分的各种眼病的新治疗方式。

DESCRIPTION: Angiogenesis is required for proper development of the embryonic circulatory system and is an important step in the progression of many eye diseases, including retinopathy of prematurity (ROP). Therefore, understanding how the normal regulatory systems in the endothelium keep angiogenesis in check has great clinical implications. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an important regulator of angiogenesis. We have shown that multiple isoforms of PECAM-1 are expressed in vascular beds of different tissues in a developmentally regulated fashion. The ability of these isoforms to differentially activate intracellular signaling pathways suggests specific roles for these isoforms during vascular development and angiogenesis. However, the physiological role PECAM-1 and its isoforms play in these processes requires further investigation. The main objective of this proposal is to delineate the physiological role of PECAM-1 and its isoforms in retinal vascular development and angiogenesis, as well as in regulation of retinal EC adhesive and migratory properties, and to elucidate the function of genes whose endothelium expression is differentially regulated by PECAM-1. Specifically, we will demonstrate the role of PECAM-1 in the development of retinal vasculature and neovascularization and determine how these processes are affected in the absence of PECAM-1. We will determine the expression pattern of PECAM-1 isoforms during retinal vascular development and neovascularization, as well as in retinal endothelial cells (EC). We will evaluate the specific roles of PECAM-1 isoforms in the regulation of EC adhesion and migration. To further elucidate PECAM-1's mechanism of action, we will identify and perform functional studies of genes such as endoglin and connective tissue growth factor whose endothelium-specific expression is differentially affected by the lack of PECAM-1. These studies will provide insight into the physiological role of PECAM-1 in retinal vascular development and angiogenesis and in modulation of EC adhesion and migration. This knowledge will be instrumental in the development of new treatment modalities for a variety of eye diseases with a neovascular component.