A zebrafish model for studying orbital development and disease

用于研究眼眶发育和疾病的斑马鱼模型

• 批准号: 7743747
• 负责人: Alon Kahana
• 金额: $ 20.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743747
• 关键词: Adipocytes; Adult; Affect; American; Anatomy; Animal Model; Antisense Oligonucleotides; Behavior; Biological; Biological Models; Biology; Blindness; Cells; Cellular biology; Chronic; Cicatrix; Compartment syndromes; Congenital Heart Defects; Cornea; Defect; Development; DiGeorge Syndrome; Diagnosis; Diagnostic; Diplopia; Disease; Embryology; Embryonic Development; Exophthalmos; Eye; Eye Development; Eye diseases; Fatty acid glycerol esters; Fetal Alcohol Syndrome; Fibroblasts; Fibrosis; Fluorescent Dyes; Forms Controls; Genes; Genetic; Genetic Markers; Glaucoma; Goals; Headache; Hyaluronan; Immunohistochemistry; In Situ Hybridization; Inflammatory; Injection of therapeutic agent; Lead; Light; Mediating; Messenger RNA; Molecular Genetics; Muscle; Neural Crest; Neural Crest Cell; Ocular orbit; Operative Surgical Procedures; Orbital Diseases; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Population; Process; Proliferating; Proteins; Public Health; Quality of life; Research; Research Project Grants; Risk; Signal Pathway; Signal Transduction; Skin; Steroids; Study models; Swelling; Techniques; Testing; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Time; Tissues; Transgenic Organisms; Zebrafish; autoimmune thyroid disease; cell type; eye dryness; eye transplantation; improved; insight; lipid biosynthesis; melanoma; migration; novel; ocular neurofibromatosis; optic nerve disorder; orbit muscle; overexpression; productivity loss; promoter; research study; stem cell population; thyroid associated ophthalmopathies; tool

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.

描述（由申请人提供）：甲状腺相关的眼病（TED）是重要的公共卫生负担，可导致生产力丧失并降低生活质量。 TED会导致长期衰弱的疼痛和头痛，双视力，角膜暴露，干眼，继发性青光眼和压缩视神经神经病，并带有明显的视力丧失风险。 TED的发病机理尚不完全理解，但涉及未鉴定的甲状腺相关细胞信号激活轨道成纤维细胞。活化的成纤维细胞又分泌大量的透明质酸，导致轨道组织肿胀，尤其是眼外肌肉。另外，轨道成纤维细胞介导导致轨道纤维化的严重炎症轨道病。轨道成纤维细胞也可以扩散并分化为脂肪细胞，从而充满多余的脂肪。组织肿胀，疤痕和脂肪形成的结合导致了骨膜和室综合征，从而正常的轨道组织被异常的轨道组织压缩，从而导致抗压神经病，继发性青光眼和慢性轨道头痛。分娩可导致慢性干眼和角膜暴露。肌肉的肿胀和纤维化可能导致眼部错位和复视。 轨道成纤维细胞是神经rest的衍生物，神经波峰是多能细胞的瞬时种群，在胚胎发生过程中分化为广泛的组织。 TED中轨道成纤维细胞的独特行为可能部分是由其胚胎神经rest起源引起的。该项目的主要假设是，在轨道神经rest发育过程中发生的胚胎过程在TED的发病机理中很重要。轨道神经rest的生物学尚不清楚，并且在很大程度上没有探索。该研究项目的目的是利用斑马鱼中可用的遗传和细胞生物学工具，为轨道神经rest衍生的组织的遗传学和细胞生物学提供了新的启示，以改善TED和其他轨道疾病的诊断和治疗。 与甲状腺相关的眼科疾病是重要的公共卫生负担，会导致生产力丧失和生活质量降低。这项研究的目的是利用斑马鱼（一种脊椎动物模型系统）中可用的遗传和细胞生物学工具，以对轨道神经crest衍生的组织的生物学发明新的启示，以改善TED和其他轨道疾病的诊断和治疗。