Genetic Models of Anterior Segment Development

眼前节发育的遗传模型

基本信息

批准号：
7729687
负责人：
D. J. SIDJANIN
金额：
$ 38万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729687
关键词：
Alleles Anterior Apoptosis Apoptosis Regulator Axon Birth Cataract Ciliary Body Cornea Corneal Endothelium Corneal Injury Corneal Stroma Defect Descemet&apos s membrane Development Developmental Process Drainage procedure Embryo Endothelium Epidermis Epithelial Epithelial Cells Epithelium Etiology Evaluation Exhibits Exons Eye Eye Development Eye diseases Eyelid structure Failure Gene Mutation Genes Genetic Genetic Models Glaucoma Goals Iris Ligand Binding Membrane Mesenchyme Microphthalmos Molecular Mus Mutation Neural Crest Neural Crest Cell Optic Nerve Paracrine Communication Pathway interactions Pattern Phenotype Play Principal Investigator Proteins Regulator Genes Regulatory Pathway Retinal Ganglion Cells Role Signal Transduction Structure Surface Ectoderm TP53 gene Tissues Western Blotting Work Wound Healing autocrine axonal guidance base cell motility corneal epithelium gene discovery human NTN1 protein inhibitor/antagonist lens loss of function mutation migration mouse model netrin-1 novel optic cup paralogous gene positional cloning public health relevance

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to identify novel genes and associated pathways involved in the development of the anterior segment. Genetic studies have contributed a great deal to our current understanding of the developmental processes as well as associated genes and pathways during the ocular development. However, many genes as well as molecular mechanisms are still unclear. To aid in the discovery of the gene/pathway/mechanism associated with anterior segment development, phenotype driven approaches have been utilized extensively. This proposal focuses on the woe and woe2 mouse models. Both woe and woe2 are autosomal recessive loci that exhibit the eyelid open at birth (EOB) phenotype, microphthalmia/anopthalmia, cataracts and defects in the anterior segment structures originating from the neural crest (NC) cells. The woe2 mice unlike woe exhibit optic nerve hypoplasia. Both mice exhibit the wavy fur phenotype. Based on the phenotypic similarities, we hypothesized that woe and woe2 genes play a role in overlapping molecular pathways essential for ocular development. By applying the positional cloning strategies we identified genes and mutations responsible for woe and woe2. The woe mice carry a hypomorphic mutation in the Adam17 gene whereas the woe2 mice carry a deletion in the Ppp1r13l gene. The goal of this proposal is to understand the role of Adam17 and Ppp1r13l during the eye development. The Specific Aim 1 focuses on evaluation of Adam17 role during the embryonic eyelid closure, development of NC-derived anterior structures and a role of Adam17 during corneal wound healing. The Specific Aim2 focuses on evaluation of the role of Ppp1r13l during embryonic eyelid closure, anterior segment development and the role of Ppp1r13l during optic nerve development. This approach will provide novel information about the functions of Adam17 and Ppp1r13l and the associated pathways during anterior segment development. PUBLIC HEALTH RELEVANCE: This proposal focuses on the identification of novel regulatory genes and the pathways governing the anterior segment development. In order to better understand the etiology of common anterior segment eye diseases such as cataracts and glaucoma, it is essential that we gain a better understanding about the mechanisms that play a central role during development.

描述（由申请人提供）：该提案的总体目标是识别前段发展中涉及的新基因和相关途径。遗传研究为我们目前对眼部发育过程中相关的基因和途径的理解做出了很大的贡献。但是，许多基因以及分子机制仍然不清楚。为了帮助发现与前部发育相关的基因/途径/机制，已广泛利用了表型驱动的方法。该提案着重于祸患和WOE2鼠标模型。祸和WOE2都是常染色体隐性位点，在出生时表现出眼睑（EOB）表型，微观心理/Anopthalmia，源自神经Crest（NC）细胞的前部段中的白内障和缺陷。 WOE2小鼠与祸害表现出视神经性发育不全。两只小鼠都表现出波浪状的皮草表型。基于表型相似性，我们假设祸害和WOE2基因在重叠眼部发育必不可少的分子途径中起作用。通过应用位置克隆策略，我们确定了导致祸害和WOE2的基因和突变。祸小鼠在ADAM17基因中携带肌电突变，而WOE2小鼠在PPP1R13L基因中携带缺失。该提议的目的是了解ADAM17和PPP1R13L在眼睛发育过程中的作用。具体目的1的重点是评估ADAM17在胚胎眼睑闭合期间的作用，NC衍生的前结构的发展以及ADAM17在角膜伤口愈合过程中的作用。具体的AIM2专注于评估PPP1R13L在胚胎眼睑闭合，前部的发育以及PPP1R13L在视神经发育过程中的作用的作用。这种方法将提供有关ADAM17和PPP1R13L功能以及在前段开发过程中相关途径的新信息。公共卫生相关性：该提案的重点是识别新型监管基因和管理前部开发的途径。为了更好地理解常见前部门眼部疾病（例如白内障和青光眼）的病因，我们必须更好地了解在发育过程中起着核心作用的机制。