Mouse model for eyelid disease: Congenital blepharophimosis

眼睑疾病小鼠模型：先天性睑裂

基本信息

批准号：
8531945
负责人：
CHIA-YANG LIU
金额：
$ 37.29万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8531945
关键词：
Actins Address Affect Amblyopia Animal Model Ankle Antibodies Binding Biological Assay Birth Blepharophimosis Boxing Cell Culture Techniques Cell Line Cells Code Complex Congenital Disorders Data Defect Dermis Development Differentiation Antigens Down-Regulation Doxycycline ES01 Embryo Enhancers Epidemiologic Studies Epidermis Exhibits Eye Eyelid Diseases Eyelid structure Fetus Gene Expression Gene Expression Regulation Gene Mutation Gene Structure Gene Targeting Genes Genetic Genetic Recombination Genetic Transcription Goals Hereditary Disease Homologous Gene Human Hyperopia Immunoglobulin binding proteins Impairment Infertility Instruction Knowledge Lazy Eyes Lead Luciferases Mammals Manganese Superoxide Dismutase Mediating Mesenchymal Molecular Morphogenesis Mouse Strains Movement Mus Muscle Muscle Development Mutation Myopia Neural Crest Outcome Outcome Study Ovarian Ovary Oxidative Stress Pathogenesis Pathway interactions Phenotype Physiologic pulse Play Premature Ovarian Failure Principal Investigator Process Protein Region Proteins Ptosis Regulation Research Risk Role Signal Transduction Smooth Muscle Staging Strabismus Stress Stromal Cells Structure Syndrome Testing Transfection Transgenic Mice Vision Visual system structure Woman calponin chromatin immunoprecipitation craniofacial forkhead protein gender preference granulose loss of function malformation meibomian gland mouse model notch protein novel ocular surface programs promoter protein expression vector

项目摘要

DESCRIPTION (provided by applicant): Blephar-ophimosis, Ptosis, and Epi-canthus inversus Syndrome (BPES) is an autosomal dominant genetic disorder characterized by craniofacial defects that mainly affect the development of the eyelids. There are two types of BPES: Type I consists of the four major features of blepharophimosis, ptosis, epicanthus inversus, and telecanthus plus premature ovarian failure (POF), leading to infertility in woman. Type II consists of only the eyelid malformations without gender preference. People with BPES are at an increased risk of developing vision problems such as nearsightedness (myopia) or farsightedness (hyperopia). They may also have eyes that do not point in the same direction (strabismus) and lazy eye (amblyopia) affecting one or both eyes. Mutations in the transcription factor forkhead box L2 (FOXL2) structure gene cause 70 percent of BPES. The FOXL2 gene provides instructions for making a protein that is involved in the development of the eyelids and the ovaries before birth. Approximately 30 percent of people with BPES do not have an identified FOXL2 structure gene mutation; the cause of the condition in these people is unknown but FOXL2 gene regulation maybe altered. Herein, we have investigated the effects of Notch1 signaling activation in peri-ocular mesenchymal cells (POMC) which contribute to the formation of the lid-specific structures including levator M¿ellersmooth muscle, tarsus, and meibomian glands. Notch1 intracellular domain (N1-ICD) was conditionally mis-expressed in POMC (here refer to as POMCN1-ICD) of a novel triple transgenic mouse strain, namely Kera-rtTA/tetO-Cre/R26floxedN1-ICD (KR/TC/R26fN1- ICD), by pulse induction of doxycycline (Dox) at different developmental stages. These triple KR/TC/R26fN1-ICD mice exhibited variegation of eyelid anomalies resembling BPES in humans. Our preliminary data showed that N1-ICD expression caused specific reduction of FoxL2 and smooth muscle differentiation marker gene, alpha-smooth actin (a-SMA) expressions in POMCs during eyelid morphogenesis. Our preliminary studies allow us to propose the hypotheses that sustained Notch signaling disturbs the formation of levator M¿eller smooth muscle responsible for eyelid opening by down-regulation of FoxL2 in the POMC cells. In this application, we will further characterize KR/TC/R26fN1-ICD triple transgenic mouse as a novel animal model to study the pathogenesis of congenital BPES (Aim1). We will also delineate a molecular pathway that leads to the down-regulation of FoxL2 and subsequent malformation of the levator M¿ellersmooth muscle during embryonic eyelid development (Aim2).

描述（由申请人提供）：睑裂、下垂和内眦综合症（BPES）是一种常染色体显性遗传性疾病，其特征是颅面缺陷，主要影响眼睑的发育。 BPES 有两种类型： I 型。由睑裂、下垂、内眦赘皮、外眦赘皮加上卵巢早衰四大特征组成患有 BPES 的人出现视力问题（例如近视）或远视（远视）的风险增加。眼睛不指向同一方向（斜视）和弱视（弱视），影响一只或两只眼睛转录因子叉头框 L2 的突变。 (FOXL2) 结构基因导致 70% 的 BPES FOXL2 基因提供了制造参与眼睑和卵巢发育的蛋白质的指令，大约 30% 的 BPES 患者没有已确定的 FOXL2 基因结构。这些人的病症的原因尚不清楚，但 FOXL2 基因调控可能发生改变。在此，我们研究了 Notch1 信号激活对眼周的影响。间充质细胞 (POMC) 有助于形成眼睑特异性结构，包括提肌 M¿ Notch1 细胞内结构域 (N1-ICD) 在新型三重转基因小鼠品系 Kera-rtTA/tetO-Cre/ 的 POMC（此处称为 POMCN1-ICD）中条件性错误表达。 R26floxedN1-ICD (KR/TC/R26fN1- ICD)，通过强力霉素脉冲诱导(Dox) 在不同的发育阶段，这些三重 KR/TC/R26fN1-ICD 小鼠表现出类似于人类 BPES 的多种眼睑异常。我们的初步数据表明，N1-ICD 表达导致 FoxL2 和平滑肌分化标记基因 α 的特异性减少。 -眼睑形态发生过程中 POMC 中的平滑肌动蛋白 (a-SMA) 表达使我们能够提出这样的假设：持续的 Notch 信号传导会干扰形成。提肌 M¿通过下调 POMC 细胞中 FoxL2 负责眼睑张开的平滑肌在本申请中，我们将进一步表征 KR/TC/R26fN1-ICD 三重转基因小鼠作为研究先天性 BPES 发病机制的新型动物模型。）我们还将描述导致 FoxL2 下调和随后提肌 M 畸形的分子途径。胚胎眼睑发育过程中的埃勒平滑肌（Aim2）。