The Roles of Notch and BMP Signaling in Anterior Segment Dysgenesis

Notch 和 BMP 信号在眼前节发育不全中的作用

• 批准号: 9049139
• 负责人: Rebecca Lynn Rausch
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049139
• 关键词: Address; Adhesions; Adult; Aging; Alleles; Anterior; Anterior eyeball segment structure; Aqueous Humor; Area; Attenuated; BMP4; Child; Childhood; Ciliary Body; Ciliary epithelium; Cornea; Cytomegalovirus; Data; Defect; Development; Developmental Biology; Disease; Drainage procedure; Exhibits; Eye; Eye Development; Eye diseases; Eyedrops; Fellowship; Fetal Development; Future; Genes; Genetic; Glaucoma; Health; Histology; Human; Hydrophthalmos; Image; Iris; Knock-out; Laboratories; Ligands; Liquid substance; Literature; Long-Term Effects; Maintenance; Measurement; Molecular; Molecular Target; Monitor; Morphogenesis; Mus; Notch Signaling Pathway; Ocular Physiology; One-Step dentin bonding system; Outcome; Pathway interactions; Pattern; Physiologic Intraocular Pressure; Physiological; Play; Prevention; Process; Production; Proteins; Pupil; Reading; Regulation; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Site; Structure; Structure of sinus venosus of sclera; Tamoxifen; Testing; Therapeutic Intervention; Tissues; Trabecular meshwork structure; Vision; Work; aqueous; bone morphogenic protein; early childhood; gene function; high intraocular pressure; histological image; insight; interest; lens; loss of function; malformation; mouse model; mutant; notch protein; public health relevance; receptor; research study; therapeutic target

 DESCRIPTION (provided by applicant): The anterior segment of the eye comprises structures essential for vision and overall ocular health. Anterior segment dysgenesis (ASD) refers to a broad spectrum of eye diseases that occur when these structures do not form appropriately during fetal development. Children born with ASD can exhibit iris hypoplasia, misplaced pupils, hazy corneas, and corneal-iris adhesions. In addition, because the tissues responsible for intraocular pressure (IOP) regulation reside in the anterior segment, ASD is commonly associated with a severe form of childhood glaucoma - a progressive blinding disease for which increased IOP is the leading risk factor. Though early malformation of the anterior segment is known to result in a variety of eye disorders, the specific mechanisms underlying its proper development remain largely unidentified. Recent data has implicated both Notch and Bone Morphogenic Protein (BMP) signaling in the formation of the ciliary body, the site of aqueous fluid production. Specifically, in mice deficient for the Notch2 receptor, BMP signaling was significantly diminished and the ciliary body failed to develop. Furthermore, preliminary evidence suggests that these pathways may also be involved in development of the iridocorneal angle, a region involved in fluid drainage comprised of the trabecular meshwork and Schlemm's canal. The experiments proposed below will test the overarching hypothesis that Notch signaling acts upstream of BMP signaling in the development of anterior segment structures important for IOP regulation. Using mouse gain and loss of function alleles, I will examine the morphogenesis of the ciliary body and iridocorneal angle following perturbation of key proteins within the pathways of interest. In addition, I will assess the long-term effects of ASD on ocular physiology in adult mice. This work will define the temporal and spatial requirements of the Notch and BMP signaling pathways during the formation and later maintenance of important anterior eye structures. Results from these studies will ultimately provide fundamental insight into the developmental biology regulating anterior segment development, as well as identify molecular targets that may prove valuable in treating children with ASD.

 描述（由申请人提供）：眼前节包括对视力和整体眼部健康至关重要的结构。眼前节发育不全（ASD）是指当这些结构在胎儿发育期间没有适当形成时发生的广泛的眼部疾病。先天性ASD患儿可表现为虹膜发育不全、瞳孔错位、角膜模糊和角膜虹膜粘连。此外，由于负责眼内压（IOP）调节的组织位于眼前段，ASD通常与严重形式的儿童青光眼相关-一种进行性致盲疾病，IOP升高是其主要风险因素。虽然已知眼前节的早期畸形会导致各种眼部疾病，但其正常发展的具体机制仍在很大程度上未被确定。最近的数据表明Notch和骨形态发生蛋白（BMP）信号在睫状体的形成中起作用，睫状体是水液产生的部位。具体而言，在Notch 2受体缺陷的小鼠中，BMP信号传导显著减弱，睫状体未能发育。此外，初步证据表明，这些途径也可能参与虹膜角膜角的发展，这是一个涉及由小梁网和施累姆氏管组成的液体引流的区域。下面提出的实验将测试总体假设，即Notch信号传导在对IOP调节重要的前段结构的发育中作用于BMP信号传导的上游。使用小鼠获得和功能等位基因的损失，我将检查睫状体和虹膜角膜角的形态发生后，扰动的关键蛋白质的途径内的利益。此外，我将评估ASD对成年小鼠眼部生理学的长期影响。这项工作将定义在重要的前眼结构的形成和后期维护过程中Notch和BMP信号通路的时间和空间要求。这些研究的结果最终将为调节眼前节发育的发育生物学提供基本见解，并确定可能在治疗ASD儿童中有价值的分子靶点。