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Stepwise Coordination of Eye Morphogenesis by Extracellular Matrix

细胞外基质对眼睛形态发生的逐步协调

基本信息

批准号：
10356085
负责人：
Kristen M Kwan
金额：
$ 36.98万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10356085
关键词：
Animal Model Automobile Driving Basement membrane Biological Models Bruch&apos s basal membrane structure Cell Death Cell Size Cell Survival Cell Transplantation Cell physiology Cells Chondroitin Sulfate A Chondroitin Sulfate Proteoglycan Coloboma Complex Computational Technique Computer Analysis Computing Methodologies Data Defect Deposition Development Ectoderm Embryo Environment Epithelial Event Exposure to Extracellular Matrix Eye Eye Development Focal Adhesions Four-dimensional Fresh Water Gene Expression Profiling Glycoproteins Goals Human Image Imaging Techniques Impairment In Vitro Laminin Lead Light Methods Microscopy Modeling Molecular Molecular Genetics Morphogenesis Morphology Movement Mutation Neural Crest Neural Crest Cell Neural Retina Newborn Infant Nidogen Ocular Pathology Optic vesicle Optics Organoids Pathway interactions Physiological Play Positioning Attribute Process Regenerative Medicine Retina Retinal Pigments Role Series Shapes Signal Transduction Structural defect Structure Structure of retinal pigment epithelium Tenascin Testing TimeLine Tissue Engineering Tissue Model Tissues Transplantation Visual impairment Work Zebrafish cell behavior cell motility cell type experimental study extracellular eye formation imaging modality in vivo innovation lens membrane assembly molecular dynamics optic cup progenitor programs protein crosslink response single cell sequencing spatiotemporal teleost fish versican zebrafish development

项目摘要

Project Summary Developmental defects in eye structure commonly account for visual impairment in newborns. Proper eye structure is initially established via the process of optic cup morphogenesis, during which a series of complex cell and tissue rearrangements transforms the optic vesicle into the optic cup, with neural retina and retinal pigmented epithelium (RPE) enwrapping the newly formed lens. With advances in imaging and computational analysis, work from our lab and others has begun to reveal the cellular events underlying optic cup morphogenesis, however, molecular control of these processes still remains poorly understood. A compelling candidate to play a role in controlling optic cup morphogenesis is the extracellular matrix (ECM), a complex, glycoprotein-rich layer that regulates cell survival, movement, signaling, and polarity. Mutations in certain ECM components can lead to ocular pathologies, such as coloboma, suggesting specific requirements during optic cup morphogenesis. Understanding extrinsic control of morphogenesis also has implications for organoid approaches and strategies. Our previous data indicate that a core molecule, laminin, elicits diverse cellular responses in different eye regions. We also found that separate eye domains are exposed to distinct ECM microenvironments, some of which are assembled via tissue-tissue interactions: specifically, neural crest is required to build basement membrane around the RPE. These data suggest that unique ECM microenvironments may be a crucial driver of regional eye morphogenetic events. Zebrafish provide an ideal model system to study this process: optical transparency and rapid development offer a unique opportunity to directly observe and molecularly dissect eye formation in vivo. We previously developed 4-dimensional imaging and computational techniques to track and visualize cell movements throughout optic cup morphogenesis, and recently, methods for automated quantitative analysis of retinal cell size, shape and orientation. This puts us in a unique position to analyze specific morphogenetic defects arising when particular matrix components are disrupted. In this proposal, we will dissect the region-specific roles of ECM factors, including nidogens, tenascin-C, mmp2, and versican, during eye morphogenesis. We hypothesize that dynamic, region-specific ECM microenvironments elicit unique developmental and morphogenetic responses from distinct eye progenitor domains to drive optic cup morphogenesis. Combining molecular genetics with innovative 4-dimensional live imaging and computational methods, we will test this hypothesis in the following specific aims: (1) determine how ECM microenvironment controls retina morphogenesis and organization; (2) determine how ECM modulatory factors control RPE morphogenesis; and (3) determine functional requirements for tissue contributions to specific ECM microenvironments. The experiments proposed will define the spatiotemporal dynamics of ECM activity and distinct cellular functions executed by region-specific ECM factors during crucial steps of eye formation.

项目总结