Ocular complications of CHARGE Syndrome: The role of Sox11

眼睛发育障碍与结构性出生缺陷有关，如小眼球， 无眼症和凹陷(统称为MAC)，是儿科的一个重要原因 失明。眼部异常通常与脑和颅面部缺陷同时发生，突出了 头部发育结构之间的重要信号相互作用；事实上，MAC是一种常见的 系统性先天畸形综合征的特点。一个例子是Charge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、生殖器发育迟缓为特征的眼眶疾病 异常，和耳朵异常。染色体结构域解旋酶结合蛋白7(CHD7)和 神经脊细胞发育和迁移的缺陷与Charge的发病机制有关 综合征，然而，在主要患者中观察到的眼睛出生缺陷的潜在机制 没有被确认身份。 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。 我们实验室以前的工作表明，SoxC转录家族成员sox11的敲除 斑马鱼中的因子会导致小眼炎、缺陷症、脑、躯干和心脏缺陷，所有这些都是表型 观察荷尔蒙综合征。此外，我们还发现，骨的表达需要sox11 眼发育过程中的形态发生蛋白(BMPs)。在人类中，sox11的复制已经被 在一名临床诊断为Charge综合征的患者中发现，CHD7已被证明直接 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 SOX 11的表达导致神经脊细胞动力学的中断以及BMP信号的改变 在开发过程中。这一假设将在以下目标中得到检验：1)确定sox11和 CHD7在脑神经脊细胞的分化、增殖、存活和迁移中起重要作用 确定Sox11和CHD7缺乏是否改变了颅骨BMP信号。这项提案将雇用 创新和尖端的实时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的一个重要问题 儿科遗传学。 该项目的成功完成将确定sox11在眼部发病机制中的作用。 缺陷，如在Charge综合征中观察到的缺陷，并在改善 先天性眼畸形的识别、处理和治疗。另外，这位博士后 计划书使应聘者能够培养独特的技术、批判性思维和有效的沟通技能 对于一个专门研究眼科儿科遗传学的内科科学家来说至关重要。 好了！

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. !