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 Our unpublished preliminary findings demonstrate that Notch2 and BMP signaling maintain the expression of RhoA in the CB, and that RhoA is also important for CB morphogenesis.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.

项目概要 眼前节发育不全 (ASD) 是指影响前节结构的一系列疾病。 眼睛的一部分，包括虹膜、睫状体 (CB)、角膜和小梁网。大约50% 的自闭症谱系障碍 (ASD) 患者会患上青光眼。它还可能伴有其他系统缺陷，例如 阿拉吉尔综合症。然而，自闭症谱系障碍的分子和细胞机制在很大程度上仍然难以捉摸。 这项研究旨在研究形态发生背后的发育机制 CB，前段的一部分。 CB 有两个重要的生物学功能：晶状体调节和 分泌房水以维持眼内压（IOP）。高眼压与以下风险相关： 青光眼，而晶状体调节缺陷会导致近视或近视。本次活动的长远目标 该项目旨在更好地了解 Notch 信号传导如何控制正常的 CB 形态发生和 分泌。这项拟议的研究基于我们最近令人兴奋的发现，即 Notch2 控制 CB 形态发生， 发表在 PNAS (2013) 上。我们未发表的初步研究结果表明，Notch2 和 BMP 信号传导维持 CB 中 RhoA 的表达，并且 RhoA 对于 CB 形态发生也很重要。 这项研究的三个具体目标是：(1) 调查 Jag1 和 Dll1 是否激活 Notch2 和 Notch3 控制CB形态发生； (2) 研究Notch调节的BNP信号如何通过以下方式控制CB形态发生 促进 OCE 中 RhoA 蛋白的表达； (3) 研究Dll1-Notch3信号是否控制CB分泌 通过 Rbpj 依赖机制。 Jag1-Notch2 信号传导缺陷会导致 Alagille 综合征，从而影响 人类眼睛的前段、肝脏、肺和脉管系统，但潜在的细胞机制 仍然很大程度上不为人所知。因此，这项研究将增强我们理解分子的能力 青光眼、近视和 Alagille 综合征发病机制的细胞机制，并将 帮助找到更好的疾病治疗方法。