Ocular complications of CHARGE Syndrome: The role of Sox11

CHARGE 综合征的眼部并发症：Sox11 的作用

• 批准号: 10704036
• 负责人: Laura Krueger
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704036
• 关键词: Anophthalmos; Binding Proteins; Biochemical; Biological Models; Blindness; Bone Morphogenetic Proteins; Brain; CHARGE syndrome; CHD7 gene; Cephalic; Childhood; Choanal Atresia; Chromatin; Chromosomal Duplication; Code; Coloboma; Communication; Confocal Microscopy; Congenital Abnormality; Craniofacial Abnormalities; Critical Thinking; DNA Binding Domain; Data; Defect; Development; Disease; Ear; Eye; Eye Development; Eye diseases; Family; Fetal Development; Fluorescence-Activated Cell Sorting; Future; Genes; Genetic; Genetic Research; Genital; Genitalia; Goals; Growth; Head; Heart Abnormalities; Human; Image; Imaging Techniques; Immunoprecipitation; Inherited; Label; Laboratories; Laboratory Study; Light; Microphthalmos; Microscopy; Modeling; Molecular Biology; Morphogenesis; Mutation; Names; Neural Crest Cell; Pathogenesis; Pathway interactions; Patients; Phenotype; Physicians; Play; Process; Proliferating; Proteins; Regulation; Reporter; Reporter Genes; Research; Research Ethics; Role; SOX11 gene; SOX4 gene; Scientist; Signal Pathway; Signal Transduction; Signaling Protein; Specific qualifier value; Structural Congenital Anomalies; Structure; Syndrome; Systems Development; Testing; Training; Transcription Coactivator; Transgenic Organisms; Visual System; Visual impairment; Work; Zebrafish; clinical diagnosis; clinical phenotype; developmental genetics; eye formation; helicase; improved; innovation; knock-down; malformation; member; migration; mutant; nerve stem cell; neural; novel therapeutics; pre-doctoral; preservation; sex; sight restoration; skills; sry Genes; transcription factor; vision development

Disruptions in eye development are associated with structural birth defects such as microphthalmia, anophthalmia, and coloboma (collectively referred to as MAC), and are a significant cause of pediatric blindness. Ocular abnormalities often occur alongside those of brain and craniofacial defects, highlighting the significant signaling interactions between the developing structures of the head; indeed, MAC is a common feature of systemic congenital malformation syndromes. One example is CHARGE syndrome, a genetic neural cristopathy characterized by coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Mutations in chromodomain helicase binding protein 7 (CHD7) and defects in neural crest cell development and migration have been implicated in the pathogenesis of CHARGE syndrome, however the mechanisms underlying the ocular birth defects observed in CHARGE patients have not been identified. Our laboratory studies the development of the vertebrate visual system using zebrafish (Danio rerio). Previous work from our lab has shown that knockdown of Sox11, a member of the SoxC family of transcription factors, in zebrafish results in microphthalmia, coloboma, brain, trunk, and heart defects, all phenotypes observed in CHARGE syndrome. Furthermore, we found that Sox11 is required for the expression of Bone morphogenic proteins (BMPs) during ocular development. In humans, a duplication of Sox11 has been identified in a patient clinically diagnosed with CHARGE syndrome, and CHD7 has been shown to directly interact with Sox11 and Sox4 in neural stem cells. Based on these data, my central hypothesis is that the loss of Sox 11 expression leads to disruptions in neural crest cell dynamics as well as alterations in BMP signaling during development. This hypothesis will be tested in the following aims 1) Determine the role that Sox11 and Chd7 play in the specification, proliferation, survival, and migration of cranial neural crest cells, and 2) Determine whether Sox11 and Chd7 deficiency alters cranial BMP signaling. This proposal will employ innovative and cutting edge live imaging techniques, as well as advanced biochemical and molecular biology approaches, and will leverage the power of the zebrafish model to tackle an important problem in ocular pediatric genetics. Successful completion of this project will define the role of Sox11 in the pathogenesis of the ocular defects such as those observed in CHARGE syndrome and make progress towards improving the identification, management, and treatment of congenital eye malformations. Additionally, this predoctoral proposal allows the candidate to develop unique technical, critical thinking, and effective communication skills crucial to a physician-scientist specializing in ophthalmic pediatric genetics. !

眼睛发育障碍与结构性出生缺陷有关，例如小眼症、 缺眼症和缺损（统称为 MAC），是小儿眼病的重要原因 失明。眼部异常通常与大脑和颅面缺陷同时发生，这凸显了 头部发育结构之间存在显着的信号相互作用；事实上，MAC是一个常见的 全身性先天畸形综合征的特点。一个例子是 CHARGE 综合征，这是一种遗传性神经病 以缺损、心脏缺陷、后鼻孔闭锁、生长迟缓、生殖器为特征的鼻窦病 异常，以及耳朵异常。染色质结构域解旋酶结合蛋白 7 (CHD7) 和 神经嵴细胞发育和迁移的缺陷与 CHARGE 的发病机制有关 综合征，然而，在 CHARGE 患者中观察到的眼部出生缺陷的潜在机制 未被识别。 我们的实验室利用斑马鱼（Danio rerio）研究脊椎动物视觉系统的发育。 我们实验室之前的工作表明，Sox11（SoxC 转录家族的成员）的敲低 因素，在斑马鱼中导致小眼症、缺损、大脑、躯干和心脏缺陷，所有表型 在 CHARGE 综合征中观察到。此外，我们发现Bone的表达需要Sox11 眼睛发育过程中的形态发生蛋白（BMP）。在人类中，Sox11 的重复已被证实 在临床诊断为 CHARGE 综合征的患者中发现，CHD7 已被证明可以直接 与神经干细胞中的 Sox11 和 Sox4 相互作用。根据这些数据，我的中心假设是损失 Sox 11 表达的减少会导致神经嵴细胞动力学的破坏以及 BMP 信号传导的改变 在开发过程中。该假设将在以下目标中进行检验 1) 确定 Sox11 和 Chd7 在颅神经嵴细胞的规范、增殖、存活和迁移中发挥作用，2) 确定 Sox11 和 Chd7 缺陷是否会改变颅骨 BMP 信号传导。本提案将采用 创新和尖端的实时成像技术，以及先进的生化和分子生物学 方法，并将利用斑马鱼模型的力量来解决眼部的一个重要问题 小儿遗传学。 该项目的成功完成将明确Sox11在眼病发病机制中的作用 诸如在 CHARGE 综合征中观察到的缺陷，并在改善 先天性眼部畸形的识别、管理和治疗。另外，这个博士前 提案使候选人能够发展独特的技术、批判性思维和有效的沟通技巧 对于专门研究眼科儿科遗传学的医师科学家来说至关重要。 ！