Ocular defects caused by TCF8/Zfhx1a mutations

TCF8/Zfhx1a 突变引起的眼部缺陷

• 批准号: 7500046
• 负责人: DOUGLAS S DARLING
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500046
• 关键词: Amblyopia; Anterior; Anterior eyeball segment structure; Apoptosis; Cataract; Characteristics; Clinical; Coloboma; Cornea; Corneal Endothelium; Corneal Opacity; Corneal dystrophy; Defect; Development; Disease; Disease regression; Embryo; Endothelial Cells; Epithelial; Eye; Eye Development; Failure; Family; Foundations; Future; Gene Targeting; Genes; Genetic; Genetic Crosses; Glaucoma; Goals; Hemorrhage; Human; Hyperplasia; Immunohistochemistry; Injection of therapeutic agent; Iris; Knockout Mice; Lead; Mediating; Metaplasia; Microphthalmos; Molecular; Mus; Mutant Strains Mice; Mutation; National Eye Institute; Numbers; Pathway interactions; Physiological; Proteins; Rate; Regulatory Pathway; Research; Retinal Degeneration; Retinal Detachment; Role; Signal Pathway; Signal Transduction; Therapeutic; Time; Tissues; Vascularization; Work; anterior chamber; base; cell type; congenital cataract; cytokine; fetal; in vivo; insight; lens; novel; prevent; programs; repaired; research study; tool; transcription factor; vision development

DESCRIPTION (provided by applicant): The overall goal of this work is to define the mechanisms that lead to the development of tissues in the anterior segment of the eye and the hyaloid vasculature. Persistent Hyperplastic Primary Vitreous (PHPV, or PFV) is a congenital ocular defect due to the failure of the embryonic vasculature of the vitreous to regress, and generates secondary glaucoma, cataracts, retinal detachment, and intravitreal hemorrhage. There is no clear understanding of the overlapping molecular pathways responsible for regression of the primary vitreous. Our preliminary studies indicate that targeted mutation of the Zfhx1a gene in mice causes an ocular defect similar to PHPV, and including defects of the cornea and metaplasia at the iridocorneal angle. This is surprising because it indicates that Zfhx1a is a critical step in a regulatory pathway essential for eye development. This is supported by the recent identification of Zfhx1a mutations in Posterior Polymorphous Corneal Dystrophy-3 (PPCD3) families. We propose to define the ocular developmental defects in Zfhx1a-null embryos, and identify the relevant molecular pathway(s). Our overall hypothesis for these studies is that Zfhx1a regulates a novel critical step in BMP-mediated oculogenesis. Specific Aim #1 will characterize the developmental defects of the eye in Zfhx1a-mutant mice. We will define the extent and timing of PHPV in Zfhx1a-null and Zfhx1a-het mice, and characterize associated defects of the cornea and iris. We will define the cell type(s) within the vitreous and cornea that are involved in the ocular defects, and investigate changes in proliferation rate and apoptosis. We will use immunohistochemistry to investigate changes in expression of potential downstream genes involved in vascularization or regression. In Specific Aim #2, we will use genetic crosses to define the relevant signaling pathways. Together, these experiments will define the critical role for Zfhx1a in development of the anterior eye, and provide a foundation and genetic tools for future studies on how the Zfhx1a pathway is integrated with other signaling pathways. The long-term goal of this work is to define signaling pathways and cytokine-based therapies for treatment of congenital eye defects, including PHPV and PPCD-3. The overall long term goal of this research is to define major molecular signaling pathways required for regression of the fetal hyaloid vasculature and genesis of the cornea. Defining the molecular mechanisms that contribute to ocular diseases in humans is a significant goal. Identification of multiple signaling pathways that direct the regression of hyaloid vasculature should allow a therapeutic approach to the treatment of Persistent Hyperplastic Primary Vitreous (PHPV) by intraocular injection. PHPV is a congenital ocular defect due to the failure of the embryonic vasculature of the vitreous to regress. A number of clinical findings are frequently associated with PHPV, including microphthalmos, glaucoma, shallowing of the anterior chamber, corneal opacity, congenital cataract, coloboma, and retinal degeneration (11-13). Even mild cases are associated with amblyopia. A very early therapeutic treatment is needed to prevent later secondary defects. This directly relates to the National Eye Institute program's goal to investigate the development of the visual system.

描述（由申请人提供）：这项工作的总体目标是定义导致眼前部分组织和透明脉管系统中组织发展的机制。由于玻璃体的胚胎脉管系统失败，并产生了继发性青光眼，白内障，视网膜脱离和玻璃体出血。对负责原代玻璃体回归的重叠分子途径没有明确的了解。我们的初步研究表明，在小鼠中靶向ZFHX1A基因的突变会导致类似于PHPV的眼部缺陷，并包括虹膜核角下的角膜和化生的缺陷。这是令人惊讶的，因为它表明ZFHX1A是眼睛发育必不可少的调节途径的关键步骤。最近在多态角膜营养不良3（PPCD3）家族中识别ZFHX1A突变的鉴定得到了支持。我们建议定义ZFHX1A-NULL胚胎中的眼部发育缺陷，并确定相关的分子途径。这些研究的总体假设是ZFHX1A调节了BMP介导的动眼作用的新型关键步骤。特定的目标＃1将表征ZFHX1A突变小鼠眼睛的发育缺陷。我们将定义ZFHX1A-NULL和ZFHX1A-HET小鼠中PHPV的程度和时机，并表征角膜和虹膜的相关缺陷。我们将定义与眼部缺陷有关的玻璃体和角膜中的细胞类型，并研究增殖率和凋亡的变化。我们将使用免疫组织化学来研究与血管化或回归有关的潜在下游基因表达的变化。在特定的目标＃2中，我们将使用遗传十字来定义相关的信号通路。这些实验将共同定义ZFHX1A在前眼开发中的关键作用，并为未来的研究提供了有关ZFHX1A途径如何与其他信号通路集成的基础和遗传工具。这项工作的长期目标是定义信号通路和基于细胞因子的疗法，用于治疗先天性眼部缺陷，包括PHPV和PPCD-3。这项研究的总体长期目标是定义胎儿透明脉管系统回归所需的主要分子信号通路和角膜的起源。定义导致人类眼部疾病的分子机制是一个重要目标。指导透明脉管系统回归的多种信号通路的鉴定应允许通过眼内注射治疗持久增生原代玻璃体（PHPV）的治疗方法。由于玻璃体的胚胎脉管系统失败，PHPV是一种先天性眼部缺陷。许多临床发现经常与PHPV相关，包括微透明，青光眼，前室浅，角膜不透明度，先天性白内障，古罗伯菌和视网膜变性（11-13）（11-13）。即使是轻度病例也与弱视有关。需要一种非常早期的治疗治疗，以防止以后的继发缺陷。这直接与国家眼科研究所计划研究视觉系统的发展有关。