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: 10227662
• 负责人: Laura Krueger
• 金额: $ 5.1万
• 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/10227662
• 关键词: Anophthalmos; Binding Proteins; Biochemical; Biological Models; Blindness; Brain; CHARGE syndrome; CHD7 gene; Cephalic; Childhood; Choanal Atresia; Chromatin; Chromosomal Duplication; Code; Coloboma; Communication; Communication Research; 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; Proteins; Regulation; Reporter; Research; Research Ethics; Role; SOX11 gene; SOX4 gene; Scientist; Signal Pathway; Signal Transduction; Signaling Protein; Structural Congenital Anomalies; Structure; Syndrome; Testing; Training; Transcription Coactivator; Transgenic Organisms; Visual impairment; Visual system structure; Work; Zebrafish; base; bone morphogenic protein; clinical Diagnosis; clinical phenotype; developmental genetics; eye formation; helicase; improved; innovation; knock-down; malformation; member; migration; mutant; nerve stem cell; novel therapeutics; pre-doctoral; preservation; relating to nervous system; 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. !

眼睛发育的干扰与结构性先天缺陷有关 Anophthalmia和Coloboma（统称称为MAC），是小儿的重要原因 失明。眼异常通常与大脑和颅面缺陷一起出现，突出显示 头部发育结构之间的显着信号相互作用；确实，Mac是一个常见 系统性先天性畸形综合征的特征。一个例子是电荷综合征，一种遗传神经 cristopaty的特征是造成山骨，心脏缺陷，choanal闭锁，生长迟缓，生殖器 异常和耳朵异常。染色体蛋白酶结合蛋白7（CHD7）的突变和 神经rest细胞发育和迁移的缺陷已与电荷发病机理有关 综合征，但是在电荷患者中观察到的眼部出生缺陷的基础机制具有 未被确定。 我们的实验室研究使用斑马鱼（Danio Rerio）的脊椎动物视觉系统的发展。 我们实验室的先前工作表明，Soxc转录家族的成员Sox11的敲低 斑马鱼中的因素导致微观心脏，造型，大脑，躯干和心脏缺陷，所有表型 观察到电荷综合征。此外，我们发现骨骼表达需要Sox11 眼部发育过程中的形态蛋白（BMP）。在人类中，Sox11的重复是 在临床诊断患有电荷综合征的患者中被鉴定出来，并且已证明CHD7直接 与神经干细胞中的Sox11和Sox4相互作用。基于这些数据，我的中心假设是损失 Sox 11的表达导致神经Crest细胞动力学的破坏以及BMP信号的改变 在开发过程中。该假设将在以下目的中进行检验1）确定Sox11和 CHD7在颅神经rest细胞的规范，增殖，生存和迁移中发挥作用，2） 确定SOX11和CHD7缺乏是否会改变颅BMP信号传导。该建议将采用 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重要问题 小儿遗传学。 该项目的成功完成将定义Sox11在眼发病中的作用 缺陷，例如在电荷综合征中观察到的缺陷，并取得了进步 先天性眼畸形的识别，管理和治疗。另外，此占主导地位 提案允许候选人发展独特的技术，批判性思维和有效的沟通技巧 对于专门从事眼科小儿遗传学的医师科学家至关重要。 呢