Extracellular matrix remodeling in ocular anterior segment development

眼前节发育中的细胞外基质重塑

基本信息

批准号：
9189617
负责人：
SUNEEL S APTE
金额：
$ 35.66万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189617
关键词：
ADAMTS9 gene Adhesions Adult Affect Alleles Anterior Back Birth Blindness Brain Candidate Disease Gene Cardiac development Cataract Categories Cell Lineage Characteristics Child Childhood Cleaved cell Cleft Palate Complex Congenital Abnormality Cornea Corneal Opacity Crystalline Lens Cultured Cells Data Defect Development Developmental Course Ectoderm Embryo Endothelial Cells Endothelium Extracellular Matrix Eye Eye Abnormalities Eye Development Eye diseases Fibronectins Gene Mutation Genes Glaucoma Glucosyltransferase Goals Human Impairment In Vitro Infant Inherited Investigation Irido-corneo-trabecular dysgenesis Knowledge Krause-Kivlin syndrome LoxP-flanked allele Mass Spectrum Analysis Mediating Mesenchyme Mesoderm Messenger RNA Metalloproteases Modeling Modification Molecular Morphogenesis Mus Mutagenesis Mutate Names Neural Crest Cell Optic Nerve Outcome Pathway interactions Peptide Hydrolases Phenotype Prevention Process Proteins Proteoglycan Proteolysis Public Health Recombinants Retina Role Site Stimulus Structure Surface Ectoderm Syndrome Thrombospondins Variant Vascular Endothelium Vesicle Vision Visual congenital cataract developmental disease fibrillin-2 functional disability knock-down lens lens morphogenesis malformation novel optic cup pressure prevent public health relevance relating to nervous system versican

项目摘要

DESCRIPTION (provided by applicant): Anterior segment dysgenesis (ASD) encompasses a variety of developmental disorders of ocular anterior segment morphogenesis, a complex process involving several cell lineages and their associated extracellular matrix (ECM). The contribution of ECM remodeling to anterior segment morphogenesis has not been the subject of prior investigation. We recently discovered that loss of a single Adamts9 allele (encoding a secreted metalloprotease) resulted in Peters anomaly (corneal leukoma and persistent lens stalk) and lens defects, including cataract. ADAMTS9 is likely a major substrate for the glucosyltransferase B3GALTL, which is mutated in human Peters plus syndrome (PPS). In PPS, extraocular birth defects, including cleft palate and cardiac development anomalies, in which ADAMTS9 had been previously implicated, accompany Peters anomaly. We hypothesize that ADAMTS9 secreted by endothelial cells of the hyaloid vasculature and by the optic cup, is required for ECM turnover and could act non-autonomously on the lens and neural crest cells to regulate anterior segment morphogenesis. ADAMTS9 cleaves the proteoglycan, versican, about which little is known during eye development, despite its role in eye disease (Wagner syndrome). Also, preliminary studies support investigation of the ECM molecules, fibronectin and fibrillin-2 as potential ADAMTS9 substrates. In aim 1 of this proposal, we will comprehensively characterize ADAMTS9 modification by B3GALTL in vitro, and the consequences of preventing this modification in cultured cells. We will define the developmental, cellular and molecular changes underlying ASD resulting from Adamts9 haploinsufficiency. In aim 2, we will use a new floxed Adamts9 allele for conditional inactivation in vascular endothelium (Tie2-Cre), and optic cup (�re), to delineate how ADAMTS9 expressed by these specific lineages drives anterior segment morphogenesis. We will specifically investigate whether ADAMTS9 interacts with and proteolytically processes versican, fibronectin, and fibrillin-2, both in vitro and in the eye. Together, these aims provide a mechanistic continuum from B3GALTL to fundamentals of eye development to molecular actions of ADAMTS9. Relevance to public health: ADAMTS9 is a novel candidate gene for Peters anomaly, PPS or its variants, and other forms of human ASD and/or congenital cataract for which causative gene mutations are unknown. It will provide answers to a hitherto ignored question, i.e. how does ECM dynamics influence early eye development and what are the key proteases that modify the ECM? It will advance fundamental knowledge of ocular and lens morphogenesis that is highly relevant to ASD, childhood glaucoma and cataract, and provides mechanisms pertinent to the formation and possibly, the prevention of adult glaucoma and cataracts.

描述（由申请人提供）：眼前节发育不全（ASD）涵盖眼眼前节形态发生的多种发育障碍，这是一个涉及多种细胞谱系及其相关细胞外基质（ECM）的复杂过程。ECM重塑对眼前节形态发生的贡献。我们最近发现单个 Adamts9 等位基因（编码分泌型金属蛋白酶）的丢失导致了 Peters 异常（角膜白血病）。和持续性晶状体柄）和晶状体缺陷，包括白内障，ADAMTS9 可能是葡萄糖基转移酶 B3GALTL 的主要底物，该酶在人类 Peters plus 综合征（PPS）、眼外出生缺陷（包括腭裂和心脏发育异常）中发生突变。其中 ADAMTS9 先前已与 Peters 异常相关，我们捕获了由玻璃体内皮细胞分泌的 ADAMTS9。 ADAMTS9 是 ECM 周转所必需的，并且可以非自主地作用于晶状体和神经嵴细胞以调节眼前节形态发生。此外，初步研究支持对 ECM 分子、纤连蛋白和原纤维蛋白 2 作为 ADAMTS9 潜在底物的研究。在本提案的第 1 部分中，我们将在体外全面描述 B3GALTL 对 ADAMTS9 的修饰，以及在培养细胞中防止这种修饰的后果。我们将定义 Adamts9 单倍剂量不足导致的 ASD 的潜在发育、细胞和分子变化。使用新的 floxed Adamts9 等位基因对血管内皮 (Tie2-Cre) 和视杯 (�re) 进行条件失活，以描述如何这些特定谱系表达的 ADAMTS9 驱动眼前节形态发生，我们将在体外和眼中专门研究 ADAMTS9 是否与多功能蛋白聚糖、纤连蛋白和原纤维蛋白-2 相互作用并进行蛋白水解处理，这些目标共同提供了从 B3GALTL 到 B3GALTL 的机制连续体。眼睛发育的基础知识与 ADAMTS9 分子作用的关系：ADAMTS9 是 Peters 的一个新候选基因。它将为迄今为止被忽视的问题提供答案，即 ECM 动态如何影响早期眼睛发育以及关键是什么。它将极大地推进与自闭症谱系障碍（ASD）、儿童青光眼和白内障相关的眼和晶状体形态发生的基础知识，并提供与形成和白内障相关的机制。可能可以预防成人青光眼和白内障。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Selective Extracellular Matrix Proteomics Approach Identifies Fibronectin Proteolysis by A Disintegrin-like and Metalloprotease Domain with Thrombospondin Type 1 Motifs (ADAMTS16) and Its Impact on Spheroid Morphogenesis.

选择性细胞外基质蛋白质组学方法通过具有血小板反应蛋白 1 型基序 (ADAMTS16) 的解整合素样和金属蛋白酶结构域 (ADAMTS16) 鉴定纤连蛋白的蛋白水解作用及其对球体形态发生的影响。

DOI：
发表时间：
2018-07
期刊：
影响因子：
0
作者：
Schnellmann, Rahel;Sack, Ragna;Hess, Daniel;Annis, Douglas S;Mosher, Deane F;Apte, Suneel S;Chiquet
通讯作者：
Chiquet

A novel pathogenic missense ADAMTS17 variant that impairs secretion causes Weill-Marchesani Syndrome with variably dysmorphic hand features.

一种损害分泌的新型致病性错义 ADAMTS17 变异会导致 Weill-Marchesani 综合征，并伴有不同程度的手部特征畸形。

DOI：
发表时间：
2020
期刊：
影响因子：
4.6
作者：
Evans, Daniel R;Green, Jane S;Fahiminiya, Somayyeh;Majewski, Jacek;Fernandez, Bridget A;Deardorff, Matthew A;Johnson, Gordon J;Whelan, James H;Hubmacher, Dirk;Apte, Suneel S;Care4Rare Canada Consortium;Woods, Michael O
通讯作者：
Woods, Michael O

ADAMTS proteins in human disorders.

人类疾病中的 ADAMTS 蛋白。