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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

基本信息

批准号：
7505648
负责人：
DEBASISH SINHA
金额：
$ 41万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7505648
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Amino Acids Animal Model Appendix Arteries Astrocytes Base Pairing Binding Biological Assay Birth Blood Vessels Blood capillaries Cataract Cell Survival Cell physiology Cells Chemotaxis Child Chromosomes, Human, Pair 10 Chronic Clinical Closure Coculture Techniques Condition Confocal Microscopy Crystallins Culture Media Data Development Disease Disease regression Employee Strikes Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Exhibits Exons Extracellular Signal Regulated Kinases Eye Eye Abnormalities Failure Gene Mutation Genes Glial Fibrillary Acidic Protein Glycine Hemorrhage Heterozygote Homozygote Hour Human Immigration Immunohistochemistry In Situ Hybridization Intermediate Filaments Lens Fiber MAPK3 gene Measures Mediating Membrane Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modeling Molecular Mutation Neural Retina Nuclear Pathway interactions Patients Pericytes Phenotype Phosphatidylinositols Phosphotransferases Photography Platelet-Derived Growth Factor Play Protein Kinase Proteins Public Health Publishing Rat-1 Rattus Recurrence Reporting Retina Retinal Diseases Role Sprague-Dawley Rats Stimulus Structure Surface Tandem Repeat Sequences Techniques Testing Therapeutic Thinking Threonine Touch sensation Tube Up-Regulation Uveitis Vascular Endothelial Growth Factors Vascular System Vimentin Vitreous humor Western Blotting Yeasts aqueous base capillary cell motility developmental disease fetal fiber cell human disease insight intracellular protein transport lens lens protein migration mouse model mutant nestin protein novel prevent protein localization location research study response size time use yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Persistent fetal vasculature (PFV) is a human disease that results from a failure of the fetal vasculature to regress. It is a common congenital developmental disorder of the eye found in an otherwise normal child. The underlying cause of PFV disease is not well understood. We previously described a naturally occurring mutation (Nuc1) in the Sprague-Dawley rat with a novel eye phenotype involving cataract, retention of fetal vasculature, and developmental abnormalities in the retina. In Nuc1 there is failure of regression of the entire fetal intraocular vasculature and not just part of it, as reported in several other mouse models of PFV. We recently reported that the mutation causing Nuc1 is a 27 base pair insertion in exon 6 of the 2A3/A1-crystallin gene on rat chromosome 10. The 27 base pair insertion is composed of near-perfect tandem repeats of a 7 base pair sequence, TGACTAT. This in-frame insertion results in the loss of a universally conserved glycine residue in exon 6 and its replacement with 10 new amino acids. We demonstrated that in the neural retina, 2A3/A1-crystallin is expressed only in the astrocyes. In the Nuc1 rat, astrocytes surround the retained vessels as is found in other animal models of PFV. However, astrocytes are not associated with the hyaloid vasculature in the normal eye. While 2A3/A1-crystallin is entirely cytoplasmic in lens, the protein is largely nuclear in astrocytes. Both lens fibers and astrocytes from Nuc1 homozygotes show striking structural abnormalities with profound effects on the expression and organization of intermediate filaments (IFs). We have demonstrated that both the astrocytes associated with the fetal vasculature and the lenses in Nuc1 rats and PFV patients express increased amounts of VEGF. Based on these findings, we hypothesize that mutation of 2A3/A1- crystallin causes abnormal association of astrocytes with the hyaloid artery, which inhibits regression of the fetal vasculature. To test this hypothesis, the following specific aims are proposed: AIM1: To characterize and compare 2A3/A1-crystallin expression in wildtype and in Nuc1 homozygous rats during lens fiber cell and astrocyte development. AIM2: To investigate if altered motility of Nuc1 homozygous astrocytes during development contributes to the abnormal association between astrocytes and the hyaloid vasculature. AIM3: To determine if VEGF produced by astrocytes expressing mutant 2A3/A1-crystallin mediates the survival and stabilization of the hyaloid vasculature in the Nuc1 rat. We believe that the proposed studies should provide new insights into the cellular and molecular interactions that regulate hyaloid vascular regression. The possibility that 2A3/A1-crystallin may have a role in hyaloid vascular regression is important; it may help elucidate mechanisms underlying PFV that would have potential clinical implications. PUBLIC HEALTH RELEVANCE: Persistent Fetal Vasculature (PFV) is a common blinding, congenital eye disease. Our data (published and unpublished) indicate that mutant 2A3/A1-crystallin plays a role in PFV. The proposed studies may help elucidate mechanisms underlying PFV that would have potential therapeutic implications.

描述（由申请人提供）：持续性胎儿血管（PFV）是一种由胎儿血管退化失败引起的人类疾病。这是一种常见的先天性发育障碍的眼睛发现在其他正常的孩子。PFV疾病的根本原因尚不清楚。我们之前在Sprague-Dawley大鼠中描述了一种自然发生的突变（Nuc1），这种突变具有一种新的眼睛表型，涉及白内障、胎儿血管保留和视网膜发育异常。在Nuc1中，整个胎儿眼内血管的退化失败，而不仅仅是一部分，正如在其他几种PFV小鼠模型中所报道的那样。我们最近报道了引起Nuc1的突变是大鼠10号染色体上2A3/ a1结晶蛋白基因外显子6上27个碱基对的插入。27个碱基对插入是由7个碱基对序列TGACTAT的近乎完美串联重复组成的。这种框内插入导致6号外显子中普遍保守的甘氨酸残基丢失，并被10个新的氨基酸取代。我们证实，在神经视网膜中，2A3/ a1 -晶体蛋白仅在星形胶质细胞中表达。在Nuc1大鼠中，星形胶质细胞围绕着保留的血管，这在其他动物模型中也发现了。然而，在正常的眼睛中，星形胶质细胞与玻璃体血管无关。晶状体中的2A3/ a1 -晶体蛋白完全是细胞质的，而星形胶质细胞中的2A3/ a1 -晶体蛋白大部分是核的。来自Nuc1纯合子的晶状体纤维和星形胶质细胞都表现出显著的结构异常，对中间丝的表达和组织产生了深远的影响。我们已经证明，在Nuc1大鼠和PFV患者中，与胎儿脉管系统和晶状体相关的星形胶质细胞表达的VEGF量增加。基于这些发现，我们假设2A3/A1-晶体蛋白突变导致星形胶质细胞与玻璃状动脉异常关联，从而抑制胎儿血管的退化。为了验证这一假设，我们提出了以下具体目的：AIM1：表征和比较野生型和Nuc1纯合大鼠晶状体纤维细胞和星形胶质细胞发育过程中2A3/ a1 -晶体蛋白的表达。目的2：探讨发育过程中Nuc1纯合子星形胶质细胞的运动改变是否与星形胶质细胞与透明质血管的异常联系有关。目的：探讨表达突变体2A3/A1-crystallin的星形胶质细胞产生的VEGF是否介导Nuc1大鼠玻璃体血管的存活和稳定。我们相信这些研究将为研究调节玻璃状血管退化的细胞和分子相互作用提供新的见解。2A3/ a1 -晶体蛋白可能在玻璃体血管退化中起重要作用；这可能有助于阐明PFV的潜在机制，具有潜在的临床意义。公共卫生相关性：持续性胎儿脉管病（PFV）是一种常见的致盲性先天性眼病。我们的数据（已发表和未发表）表明突变体2A3/ a1 -晶体蛋白在PFV中起作用。拟议的研究可能有助于阐明PFV的潜在机制，这将具有潜在的治疗意义。