PECAM-1 and Retinopathy of Prematurity

PECAM-1 和早产儿视网膜病变

• 批准号: 7780352
• 负责人: NADER SHEIBANI
• 金额: $ 32.07万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7780352
• 关键词: Adhesives; Affect; Basement membrane; Blindness; Blood Vessels; CD31 Antigens; Cardiovascular system; Cell Adhesion; Cicatrix; Clinical; Data; Development; Disease; Embryonic Development; Employee Strikes; Endoglin; Endothelial Cells; Endothelium; Equilibrium; Exhibits; Eye diseases; Gene Expression; Genes; Goals; Growth and Development function; Infant; Investigation; Knowledge; Laboratories; Medical; Modality; Molecular; Morphogenesis; Mus; Neonatology; Oxygen; Pattern; Phenotype; Physiological; Play; Premature Infant; Process; Property; Protein Isoforms; Proteins; Regulation; Regulatory Pathway; Retina; Retinal; Retinal Detachment; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Signal Pathway; System; Tissues; United States; Vascularization; Visual impairment; Work; angiogenesis; connective tissue growth factor; density; effective therapy; gene function; insight; legally blind; migration; neovascular; neovascularization; new growth; postnatal; restoration; retina blood vessel structure; vascular bed

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.

描述：血管生成是正确发展胚胎循环系统所必需的，并且是许多眼部疾病（包括早产性视网膜病）进展的重要一步。因此，了解内皮中的正常调节系统如何控制血管生成具有很大的临床意义。血小板内皮细胞粘附分子-1（PECAM-1）是血管生成的重要调节剂。我们已经表明，PECAM-1的多种同工型以发育调节的方式在不同组织的血管床中表达。这些同工型差异激活细胞内信号通路的能力表明了在血管发育和血管生成过程中这些同工型的特定作用。但是，PECAM-1及其在这些过程中的同工型的生理作用需要进一步研究。该提案的主要目的是描述PECAM-1及其同工型在视网膜血管发育和血管生成中的生理作用，以及在视网膜EC粘附和迁移特性的调节中，阐明其内皮表达的基因功能由PECAM-1差异调节。具体而言，我们将证明PECAM-1在视网膜脉管系统发展和新血管形成中的作用，并确定在没有PECAM-1的情况下如何影响这些过程的作用。我们将在视网膜血管发育和新血管形成期间以及视网膜内皮细胞（EC）中确定PECAM-1同工型的表达模式。我们将评估PECAM-1同工型在EC粘附和迁移调节中的特定作用。为了进一步阐明PECAM-1的作用机理，我们将识别和执行诸如内聚细胞和结缔组织生长因子等基因的功能研究，其内皮特异性表达受到缺乏PECAM-1的影响。这些研究将洞悉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。这些知识将有助于开发具有新疾病的新治疗方式，并具有新的眼部疾病。