Investigation of Notch signaling in the regulation of ciliary body development and function

Notch信号在睫状体发育和功能调节中的研究

• 批准号: 9220447
• 负责人: TING XIE
• 金额: $ 41.25万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220447
• 关键词: Affect; Alagille Syndrome; Anterior; Anterior eyeball segment structure; Apical; Aqueous Humor; Biological Process; Cell Adhesion Molecules; Cell Proliferation; Ciliary Body; Ciliary epithelium; Cornea; Defect; Development; Disease; Exhibits; Extracellular Matrix Proteins; Eye; Eye diseases; F-Actin; Gene Expression; Genes; Glaucoma; Goals; Human; Investigation; Iris; Knock-out; Knowledge; Ligands; Liver; Lung; Messenger RNA; Molecular; Morphogenesis; Mus; Myopia; NOTCH3 gene; Notch Signaling Pathway; Paper; Pathogenesis; Pathway interactions; Patients; Physiologic Intraocular Pressure; Pigments; Production; Proteins; Publishing; Regulation; Risk; Risk Factors; Role; Signal Transduction; Structure; Testing; Trabecular meshwork structure; base; blind; bone morphogenetic protein receptor type I; design; developmental disease; high intraocular pressure; lens; mutant; notch protein; protein expression; rhoA GTP-Binding Protein; transcription factor; treatment strategy

Project Summary Anterior segment dysgenesis (ASD) refers to a spectrum of disorders affecting the structures in the anterior segment of the eye, including the iris, ciliary body (CB), cornea and trabecular meshwork. Approximately, 50% of the patients with ASD develop glaucoma. It can be also accompanied by other systemic defects, such as Alagille syndrome. However, the molecular and cellular mechanisms underlying ASD remain largely elusive. This proposed study is designed to investigate the developmental mechanisms underlying the morphogenesis of the CB, a part of the anterior segment. The CB has two important biological functions: lens accommodation and secretion of aqueous humor for maintaining intraocular pressure (IOP). High IOP is associated with the risk for glaucoma, whereas defective lens accommodation causes myopia or near-sightedness. The long-term goal of this project is to gain a greater understanding of how Notch signaling controls normal CB morphogenesis and secretion. This proposed study is based on our recent exciting finding that Notch2 controls CB morphogenesis, which was published in PNAS (2013). Our unpublished preliminary findings demonstrate that Notch2 and BMP signaling maintain the expression of RhoA in the CB, and that RhoA is also important for CB morphogenesis. Three specific aims of this proposed study are: (1) to investigate if Jag1 and Dll1 activate Notch2 and Notch3 to control CB morphogenesis; (2) to investigate how Notch-regulated BNP signaling controls CB morphogenesis by promoting RhoA protein expression in the OCE; (3) to investigate if Dll1-Notch3 signaling controls CB secretion through Rbpj-dependent mechanisms. Defective Jag1-Notch2 signaling causes Alagille syndrome, which affects the anterior segment of the eye, liver, lung and vasculature in humans, but the underlying cellular mechanisms remain largely unknown. Therefore, this proposed study would enhance our ability to understand the molecular and cellular mechanisms underlying the pathogenesis of glaucoma, myopia and Alagille Syndrome, and would help find better treatments for the diseases.

项目摘要 眼前节发育不全（ASD）是指一系列影响眼前节结构的疾病。 眼睛的一部分，包括虹膜、睫状体（CB）、角膜和小梁网。大约50% 的ASD患者发展为青光眼。它还可能伴随着其他系统性缺陷，例如 Alagille综合征然而，ASD潜在的分子和细胞机制仍然很难理解。 本研究旨在探讨形态发生的发育机制， CB，前段的一部分。CB具有两个重要的生物学功能：透镜调节和 用于维持眼内压（IOP）的房水分泌。高IOP与以下风险相关： 青光眼，而有缺陷的透镜调节引起近视或近视。长期目标是 该项目旨在更好地了解Notch信号如何控制正常CB形态发生， 分泌物。这项拟议的研究是基于我们最近令人兴奋的发现，即Notch 2控制CB形态发生， 发表于PNAS（2013）。我们未发表的初步研究结果表明，Notch 2和BMP 信号传导维持CB中RhoA的表达，并且RhoA对于CB形态发生也是重要的。 本研究的三个具体目的是：（1）研究Jag 1和Dll 1是否激活Notch 2和Notch 3， 控制CB形态发生;（2）研究Notch调节的BNP信号传导如何通过 促进RhoA蛋白在OCE中的表达;（3）研究Dll 1-Notch 3信号传导是否控制CB分泌 通过依赖Rbpj的机制。Jag 1-Notch 2信号传导缺陷导致Alagille综合征， 人类的眼前节、肝脏、肺和脉管系统，但其潜在的细胞机制 但基本上仍不为人所知。因此，这项拟议的研究将提高我们理解分子生物学的能力。 以及青光眼、近视和Alagille综合征发病机制的细胞机制， 帮助找到更好的治疗方法。