PECAM-1 and Retinopathy of Prematurity

血管生成是胚胎循环系统正常发育所必需的，也是包括早产儿视网膜病变（ROP）在内的许多眼病进展的重要步骤。因此，了解内皮细胞中的正常调节系统如何控制血管生成具有重要的临床意义。血小板内皮细胞粘附分子-1 （PECAM-1）是血管生成的重要调节因子。我们已经证明，PECAM-1的多种亚型在不同组织的血管床中以发育调节的方式表达。这些异构体的能力，以不同的方式激活细胞内信号通路表明，这些异构体在血管发育和血管生成中的特定作用。然而，PECAM-1及其同工异构体在这些过程中的生理作用需要进一步研究。本文的主要目的是阐明PECAM-1及其同型异构体在视网膜血管发育和血管生成中的生理作用，以及对视网膜EC粘附和迁移特性的调节，并阐明PECAM-1差异调节内皮表达的基因的功能。具体来说，我们将展示PECAM-1在视网膜血管和新生血管发育中的作用，并确定在PECAM-1缺失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以及视网膜内皮细胞（EC）中的表达模式。我们将评估PECAM-1异构体在EC粘附和迁移调控中的具体作用。为了进一步阐明PECAM-1的作用机制，我们将鉴定并对内啡肽和结缔组织生长因子等基因进行功能研究，这些基因的内皮特异性表达受到PECAM-1缺乏的不同影响。这些研究将深入了解PECAM-1在视网膜血管发育和血管生成以及EC粘附和迁移调节中的生理作用。这方面的知识将有助于开发新的治疗方式，以治疗各种眼部疾病的新血管成分。

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.