A novel bA3/A1-crystallin gene mutation results in persistent fetal vasculature

一种新的 bA3/A1-晶状体蛋白基因突变导致胎儿血管系统持续存在

• 批准号: 8715813
• 负责人: DEBASISH SINHA
• 金额: $ 47.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715813
• 关键词: Accounting; Address; Affect; Affinity Chromatography; Animals; Area; Arteries; Astrocytes; Behavior; Binding; Blood Vessels; Child; Clinical; Complex; Crystallins; Data; Defect; Development; Disease; Endothelial Cells; Etiology; Eye; Failure; Gene Mutation; Gene Targeting; Health; Human; Immigration; Investigation; Joints; Knock-out; Knowledge; Lead; Mediating; Modeling; Molecular; Morphology; Mus; Mutation; Notch Signaling Pathway; Optic Nerve; Pericytes; Play; Process; Proteins; Proteomics; Publishing; Rattus; Recycling; Research; Retina; Retinal; Role; Severities; Signal Pathway; Signal Transduction; Symptoms; Testing; Time; Tissues; Transgenic Organisms; Vascular Endothelial Growth Factors; Vascular System; Vascular remodeling; aquaporin 4; base; cell motility; developmental disease; fetal; functional loss; human disease; inhibitor/antagonist; insight; lens; migration; mouse model; mutant; notch protein; novel; novel therapeutic intervention; programs; receptor; retina blood vessel structure; secretase; therapeutic target; tool; vessel regression

DESCRIPTION (provided by applicant): During development of the mammalian eye, nourishment of the immature lens, inner retina and vitreous is provided by the hyaloid vascular system. One of the congenital, developmental disorders of the human eye, persistent fetal vasculature (PFV), results from the complete or partial failure of this vascular regression. Knowledge of the cellular and molecular mechanisms by which hyaloid vascular regression fails is very limited. Our studies have provided novel evidence that abnormalities in astrocytes during retinal development can inhibit regression of the hyaloid artery. Astrocytes ensheath the hyaloid artery in human PFV disease and in many mouse models. We have now developed novel models that mimic the clinical signs of human PFV disease. In this competitive renewal, we therefore propose, studies that will allow us to investigate: Specific Aim 1: To evaluate the impact of ¿A3/A1-crystallin on Notch signaling in retinal astrocytes. Astrocytes migrate from the optic nerve into the inner retina to form a template on which the retinal vessels will develop. A defect in the normal template formation may lead to dramatic differences in astrocyte morphology and behavior and may disrupt the normal programmed regression of the hyaloid vessels during development. The molecular signals that mediate astrocyte template formation remain elusive. Our preliminary data indicate that Notch signaling is necessary for astrocyte template formation in the retina and that A3/A1-crystallin may be a regulator of notch signaling in astrocytes. In Focus 1, we will compare the effects of -secretase inhibition in wild type astrocytes and astrocytes lacking A3/A1-crystallin, while Focus 2 will determine if A3/A1-crystallin is involved in the proteolytic release of active notch and thereby the activation of Noth target genes. Focus 3 will be to investigate a possible role for A3/A1-crystallin in Notch degradation. Specific Aim 2: To determine how loss of A3/A1-crystallin increases Aquaporin-4 in retinal astrocytes. We propose to seek direct evidence that A3/A1-crystallin regulates Aqp4 expression and astrocyte migration in the developing retina (Focus 1). It is also possible that A3/A1-crystallin does not directly regulate Aqp4, but affects Aqp4 levels through joint action with a binding partner; we will address this possibility in Focus 2. Specific Aim 3: To investigate the role of astrocytes in the abnormal retention of the hyaloid artery. Our approach will be (1) to determine whether A3/A1-crystallin regulates VEGF secretion by astrocytes and thereby contributes to vessel stabilization; (2) to investigate the possible role of pericytes in this abnormal retention of the hyaloid artery during development; and (3) to analyze the structural integrity and cellular organization of the hyaloid vessels. Our proposed investigations will help us to elucidate mechanisms whereby astrocytes play a crucial role in vascular remodeling. Understanding the molecular basis of remodeling during hyaloid regression may lead to development of novel therapeutic approaches for PFV, a potentially blinding disease in an otherwise normal child, for which there are limited treatment options at the present time.

设计（由申请人证明）：在哺乳动物眼中的发展，透明的透镜是由人眼的发育中的一种。有限的研究表明，在视网膜发育过程中，星形胶质细胞的异常可以使人类PFV疾病中的透明动脉降低透明型星体动脉。这使我们能够调查：特定目的1：评估„的影响A3/A1晶状体在视网膜星形胶质细胞中发育保持难以捉摸。 A1-Crystalllin参与了Beyby目标基因的蛋白水解释放。 A3/A1-晶状蛋白调节视网膜中的AQP4表达和星形胶质细胞迁移（焦点1）。 绑定的伴侣；我们将在焦点2中增加我们的方法分析透明血管的结构和细胞组织。