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: 10471252
• 负责人: Laura Krueger
• 金额: $ 5.18万
• 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/10471252
• 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. !

眼睛发育障碍与结构性先天缺陷有关，比如小眼症，