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Structural, mechanical, and cell biological properties of the ciliary zonule

睫状小带的结构、机械和细胞生物学特性

基本信息

批准号：
10587185
负责人：
Steven Bassnett
金额：
$ 49.92万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587185
关键词：
3-Dimensional Affect Age Aging Atomic Force Microscopy Biological Biological Assay Biology Biomechanics Blood Vessels Cataract Cells Development Diagnosis Disease Distant Dominant-Negative Mutation Ectopia Lentis Enzymes Epithelial Cells Epithelium Eye Eye diseases FBN1 Failure Fiber Fibrillin Microfibrils Funding Genes Glaucoma Glean Goals Growth Human Image In Vitro Inherited Iris Knockout Mice Knowledge Lead Lens dislocation Lung diseases Marfan Syndrome Materials Testing Measures Mechanics Modeling Molecular Mus Mutation Myopia Optics Pathology Patients Phenotype Physiologic Intraocular Pressure Play Proliferating Property Protein-Lysine 6-Oxidase Proteins Proteome Retinal Detachment Role Rupture S phase Shapes Stains Structure Surface System Techniques Tensile Strength Testing Thinness Visualization Weill-Marchesani syndrome crosslink extracellular human model insight lens mechanical stimulus molecular marker mouse model mutant null mutation postnatal pressure response skin disorder spatial relationship three dimensional structure transmission process viscoelasticity

项目摘要

Project Summary The fibers of the ciliary zonule suspend the lens on the optical axis and transmit the forces that flatten it during disaccommodation. Mutations in genes encoding zonular proteins underlie syndromic and non-syndromic conditions that affect the eye profoundly. Common ocular phenotypes include ectopia lentis (lens dislocation), cataract, axial elongation, myopia, glaucoma, and retinal detachment. The molecular composition of the zonule was recently elucidated, but the mechanism by which mutations in zonular components culminate in structural failure of the fibers is unknown. In Aim 1, therefore, three zonulopathies (Marfan Syndrome, Weill-Marchesani Syndrome, and Isolated Ectopia Lentis) will be modeled in mice. Utilizing recently developed imaging and material testing techniques, we will examine how, in each case, the structure and viscoelastic properties of the mouse zonule are affected by the presence of the mutant protein (or absence of the wild-type protein). We hypothesize that the initial pressurization of the eye is a critical step in zonule development. In Aim 2, this notion will be tested by measuring the rise in intraocular pressure in postnatal mice and determining whether pressurization of the developing eye in vitro causes precocious deployment of zonular fibers. Preliminary studies identified the cross-linking enzyme lysyl oxidase-like-1 (LOXL1) as an abundant component of the zonule proteome. In Aim 3, we propose that LOXL1-derived cross-links have a critical role in strengthening the zonule. We will test that hypothesis in a knockout mouse model. Finally, microspherophakia (i.e., the presence of a smaller and more spherical lens) is observed in Weill-Marchesani patients (who harbor mutations in LTBP2 or FBN1, zonular proteins that contribute to the tensile properties of the fibers). We hypothesize that forces exerted by the zonular fibers on the lens surface influence lens growth. In Aim 4, we will elucidate the three dimensional structure of the human zonule and correlate the distribution of proliferating lens epithelial cells with the strain fields established around zonular attachment points.

项目总结