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: 8883541
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883541
• 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.

描述（由申请人提供）：在哺乳动物眼睛的发育过程中，未成熟的晶状体、内视网膜和玻璃体的营养由玻璃体血管系统提供，这是人眼的先天性发育障碍，即持续性胎儿血管系统（PFV）。 ，这种血管消退完全或部分失败的结果对于玻璃体血管消退失败的细胞和分子机制的了解非常有限，我们的研究提供了异常的新证据。在视网膜发育期间的星形胶质细胞中，可以抑制人类 PFV 疾病和许多小鼠模型中的玻璃体动脉的退化。因此，我们建议进行以下研究： 具体目标 1：评估 A3/A1-晶状体蛋白对视网膜星形胶质细胞中 Notch 信号传导的影响。从视神经迁移到视网膜内部形成模板，视网膜血管将在该模板上发育。正常模板形成的缺陷可能导致星形胶质细胞形态和行为的显着差异，并可能破坏玻璃体血管的正常程序性退化。介导星形胶质细胞模板形成的分子信号仍然难以捉摸，我们的初步数据表明，Notch 信号对于视网膜中星形胶质细胞模板的形成是必需的，并且 A3/A1-晶状体蛋白可能是 Notch 的调节因子。在焦点 1 中，我们将比较野生型星形胶质细胞和缺乏 A3/A1-晶状体蛋白的星形胶质细胞中β-分泌酶抑制的作用，而焦点 2 将确定 A3/A1-晶状体蛋白是否参与活性缺口的蛋白水解释放。焦点 3 将研究 A3/A1-晶状体蛋白在 Notch 降解中的可能作用。 2：为了确定 A3/A1-晶状体蛋白的缺失如何增加视网膜星形胶质细胞中的 Aquaporin-4，我们建议寻找 A3/A1-晶状体蛋白调节视网膜中 Aqp4 表达和星形胶质细胞迁移的直接证据（焦点 1）。 A3/A1-crystallin 可能不直接调节 Aqp4，而是通过与 A3/A1-crystallin 的联合作用影响 Aqp4 水平。 结合伴侣；我们将在焦点 2 中讨论这种可能性。具体目标 3：研究星形胶质细胞在玻璃体动脉异常保留中的作用我们的方法是 (1) 确定 A3/A1-晶状体蛋白是否调节 VEGF 分泌。星形胶质细胞，从而有助于血管稳定；（2）研究周细胞在发育过程中玻璃体动脉异常保留中的可能作用；（3）分析其结构；我们提出的研究将帮助我们阐明星形胶质细胞在血管重塑中发挥关键作用的机制，了解玻璃体退化过程中重塑的分子基础可能会导致开发新的 PFV 治疗方法。正常儿童患有致盲性疾病，目前治疗选择有限。

项目成果

Modulating EGFR-MTORC1-autophagy as a potential therapy for persistent fetal vasculature (PFV) disease.

调节 EGFR-MTORC1-自噬作为持续性胎儿脉管系统 (PFV) 疾病的潜在疗法。

• 发表时间: 2020-06
• 影响因子: 13.3
• 作者: Yazdankhah, Meysam;Shang, Peng;Ghosh, Sayan;Bhutto, Imran A;Stepicheva, Nadezda;Grebe, Rhonda;Hose, Stacey;Weiss, Joseph;Luo, Tianqi;Mishra, Subrata;Riazuddin, S Amer;Ghosh, Arkasubhra;Handa, James T;Lutty, Gerard A;Zigler Jr, J Samuel;Sinh
• 通讯作者: Sinh

Autophagy and heterophagy dysregulation leads to retinal pigment epithelium dysfunction and development of age-related macular degeneration.

自噬和异噬失调导致视网膜色素上皮功能障碍和年龄相关性黄斑变性的发展。

• 发表时间: 2013-07
• 影响因子: 13.3
• 作者: Kaarniranta, Kai;Sinha, Debasish;Blasiak, Janusz;Kauppinen, Anu;Veréb, Zoltán;Salminen, Antero;Boulton, Michael E;Petrovski, Goran
• 通讯作者: Petrovski, Goran

The role of lipocalin-2 in age-related macular degeneration (AMD).

lipocalin-2 在年龄相关性黄斑变性 (AMD) 中的作用。

• 发表时间: 2020-03
• 作者: Ghosh, Sayan;Stepicheva, Nadezda;Yazdankhah, Meysam;Shang, Peng;Watson, Alan M;Hose, Stacey;Liu, Haitao;Weiss, Joseph;Zigler Jr, J Samuel;Valapala, Mallika;Watkins, Simon C;Sinha, Debasish
• 通讯作者: Sinha, Debasish

Role of glia in optic nerve.

神经胶质细胞在视神经中的作用。

• 发表时间: 2021
• 影响因子: 17.8
• 作者: Yazdankhah, Meysam;Shang, Peng;Ghosh, Sayan;Hose, Stacey;Liu, Haitao;Weiss, Joseph;Fitting, Christopher S;Bhutto, Imran A;Zigler Jr, J Samuel;Qian, Jiang;Sahel, José;Sinha, Debasish;Stepicheva, Nadezda A
• 通讯作者: Stepicheva, Nadezda A

Excipients of preservative-free latanoprost induced inflammatory response and cytotoxicity in immortalized human HCE-2 corneal epithelial cells.

不含防腐剂的拉坦前列素赋形剂在永生化人 HCE-2 角膜上皮细胞中诱导炎症反应和细胞毒性。

• 发表时间: 2014-12-01
• 作者: Smedowski, Adrian;Paterno, Jussi J;Toropainen, Elisa;Sinha, Debasish;Wylegala, Edward;Kaarniranta, Kai
• 通讯作者: Kaarniranta, Kai