Ocular complications of CHARGE Syndrome: The role of Sox11

眼睛发育的中断与结构性出生缺陷有关，如小眼球， 无眼症和缺损（统称为MAC），并且是儿科疾病的重要原因。 失明眼部异常通常与大脑和颅面缺陷同时发生，突出了 重要的信号相互作用之间的发展结构的头部;事实上，MAC是一个共同的 系统性先天畸形综合征的特征。一个例子是充电综合征，一种遗传神经 以缺损、心脏缺陷、后鼻孔闭锁、生长迟缓、生殖器 异常和耳朵异常。染色体结构域解旋酶结合蛋白7（CHD 7）中的突变和 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 未被确认。 本实验室以斑马鱼（Danio rerio）为研究对象，研究脊椎动物视觉系统的发育。 我们实验室以前的工作表明，敲除Sox 11，SoxC转录家族的成员， 因素，在斑马鱼中导致小眼球，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Sox 11是Bone表达所必需的。 形态发生蛋白（BMP）在眼发育过程中的作用。在人类中，Sox 11的复制已经被证明是 在临床诊断为CHARGE综合征的患者中鉴定，并且CHD 7已被证明直接 与神经干细胞中的Sox 11和Sox 4相互作用。基于这些数据，我的中心假设是， Sox 11表达的降低导致神经嵴细胞动力学的破坏以及BMP信号的改变 在发展过程中。这一假设将在以下目标中进行检验：1）确定Sox 11和 Chd 7在颅神经嵴细胞的特化、增殖、存活和迁移中的作用，以及2） 确定Sox 11和Chd 7缺陷是否会改变颅骨BMP信号传导。该提案将采用 创新和尖端的活体成像技术，以及先进的生物化学和分子生物学 方法，并将利用斑马鱼模型的力量来解决眼睛中的一个重要问题。 儿科遗传学 该项目的成功完成将确定Sox 11在眼内炎发病机制中的作用。 缺陷，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。此外，这位博士生 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 这对一个专门从事眼科儿科遗传学的医生科学家来说至关重要。 !

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. !