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

项目摘要 前段发育不全(ASD)是指影响前部结构的一系列疾病。 眼部，包括虹膜、睫状体、角膜和小梁网。大约，50% 的自闭症患者发展为青光眼。它还可能伴随着其他系统性缺陷，例如 阿拉格尔综合征。然而，ASD的分子和细胞机制在很大程度上仍然难以捉摸。 这项拟议的研究旨在探讨儿童智力发育的形态发生机制。 颈总动脉是前段的一部分。CB有两个重要的生物学功能：晶状体调节和 维持眼压(IOP)的房水分泌。高眼压与高眼压相关 青光眼，而晶状体调节缺陷会导致近视或近视。这样做的长期目标是 项目是为了更好地理解Notch信号如何控制正常的CB形态发生和 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Notch2控制CB的形态发生， 该报告发表在《美国国家科学院院刊》(2013)上。我们未发表的初步研究结果表明，Notch2和BMP 信号转导维持RhoA在CB中的表达，RhoA对CB的形态发生也很重要。 这项拟议研究的三个具体目标是：(1)调查Jag1和Dll1是否激活Notch2和Notch3以 控制CB的形态发生；(2)研究Notch调控的BNP信号如何通过 促进OCE中RhoA蛋白的表达；(3)探讨Dll1-Notch3信号是否控制CB的分泌 通过Rbpj依赖的机制。Jag1-Notch2信号缺陷导致Alagille综合征，从而影响 人类眼、肝、肺和血管的前段，但潜在的细胞机制 在很大程度上仍然不为人知。因此，这项拟议的研究将增强我们理解分子的能力。 以及青光眼、近视和Alagille综合征发病的细胞机制，并将 帮助寻找治疗这些疾病的更好方法。

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 Our unpublished preliminary findings demonstrate that Notch2 and BMP signaling maintain the expression of RhoA in the CB, and that RhoA is also important for CB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