A zebrafish model for studying orbital development and disease

描述(申请人提供)：甲状腺相关眼病(TED)是一种重要的公共卫生负担，会导致生产力下降和生活质量下降。TED可导致慢性衰弱性疼痛和头痛、复视、角膜暴露、干眼、继发性青光眼和压迫性视神经病变，并具有极大的视力丧失风险。TED的发病机制尚不完全清楚，但涉及一种未知的甲状腺相关细胞信号激活眼眶成纤维细胞。激活的成纤维细胞继而分泌大量的透明质酸，导致眼眶组织显著肿胀，尤其是眼外肌。此外，眼眶成纤维细胞介导了导致眼眶纤维化的严重炎症性眼眶病变。眼眶成纤维细胞也可以增殖和分化为脂肪细胞，使眼眶充满多余的脂肪。组织肿胀、瘢痕形成和脂肪生成的组合会导致眼球突出和间隔综合征，即正常的眼眶组织被异常的眼眶组织压缩，导致压迫性视神经病变、继发性青光眼和慢性眼眶头痛。眼球突出会导致慢性干眼症和角膜暴露。肌肉的肿胀和纤维化可能会导致眼睛不对准和复视。眼眶成纤维细胞是神经脊的衍生品，神经脊是一种瞬时的多能细胞群体，在胚胎发育过程中会分化为广泛的组织。眼眶成纤维细胞在TED中的独特行为可能部分是由其胚胎学神经脊起源引起的。这个项目的主要假设是，在眼眶神经脊发育过程中发生的胚胎学过程在TED的发病机制中是重要的。眼眶神经脊的生物学还不为人所知，而且在很大程度上还没有被探索过。这项研究项目的目标是利用斑马鱼可用的遗传和细胞生物学工具，为眼眶神经脊源性组织的遗传学和细胞生物学提供新的线索，以改进对TED和其他眼眶疾病的诊断和治疗。甲状腺相关眼病是一种重要的公共卫生负担，会导致生产力下降和生活质量下降。这项研究的目的是利用斑马鱼(脊椎动物模型系统)中可用的遗传和细胞生物学工具，为眼眶神经脊源性组织的生物学提供新的线索，以改进对TED和其他眼眶疾病的诊断和治疗。

DESCRIPTION (provided by applicant): Thyroid-related eye disease (TED) is an important public health burden that causes loss of productivity and reduces quality of life. TED can lead to chronic debilitating pain and headaches, double vision, corneal exposure, dry eyes, secondary glaucoma and compressive optic neuropathy, and carries a significant risk of vision loss. The pathogenesis of TED is incompletely understood, but involves the activation of orbital fibroblasts by an unidentified thyroid-related cell signal. Activated fibroblasts in turn secrete large quantities of hyaluronan, causing significant swelling of orbital tissues and especially extraocular muscles. In addition, orbital fibroblasts mediate a severe inflammatory orbitopathy that leads to orbital fibrosis. Orbital fibroblasts can also proliferate and differentiate into adipocytes, filling the orbit with excess fat. The combination of tissue swelling, scarring and adipogenesis leads to exophthalmos and a compartment syndrome whereby normal orbital tissues are compressed by the abnormal ones, leading to compressive optic neuropathy, secondary glaucoma and chronic orbital headaches. Exophthalmos can lead to chronic dry eyes and corneal exposure. The swelling and fibrosis of muscles can lead to ocular misalignment and diplopia. Orbital fibroblasts are derivatives of the neural crest, a transient population of pluripotent cells that differentiate into a broad range of tissues during embryogenesis. The unique behavior of orbital fibroblasts in TED may be partially caused by their embryologic neural crest origins. The main hypothesis of this project is that embryologic processes that occur during the development of the orbital neural crest are important in the pathogenesis of TED. The biology of the orbital neural crest is unknown and largely unexplored. The goal of this research project is to utilize the genetic and cell biology tools available in zebrafish to shed new light on the genetics and cell biology of orbital neural crest-derived tissues, in order to lead to improved diagnostic and treatment for TED and other orbital diseases. Thyroid-related eye disease is an important public health burden that causes loss of productivity and a reduced quality of life. The goal of this research is to utilize the genetic and cell biology tools available in zebrafish (a vertebrate model system) to shed new light on the biology of orbital neural crest-derived tissues, in order to lead to improved diagnosis and treatment for TED and other orbital diseases.