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Principal Investigator: Steven Bassnett
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $477,830
Funding agency: National Eye Institute
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.
Terms: <3-D><3-D structure><3-Dimensional><3-dimensional structure><3D><3D structure><Affect><Age><Aging><Antimorphic mutation><Assay><Atomic Force Microscopy><Bioassay><Biological><Biological Assay><Biology><Biomechanics><Blood Vessels><Cataract><Cell Body><Cells><Collagen Lysyl Oxidase><Congenital Ectopic Lens><Cutaneous Disorder><Dermatoses><Development><Diagnosis><Disease><Disorder><Distant><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><EC 1.4.3.13><Ectopia Lentis><Enzyme Gene><Enzymes><Epithelial Cells><Epithelium><Eye><Eye diseases><Eyeball><FBN1><Failure><Fiber><Fibrillin Microfibrils><Force Microscopy><Funding><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic defect><Glaucoma><Glean><Goals><Growth><Hereditary><Human><Image><In Vitro><Inherited><Intraocular Pressure><Iris><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Lead><Leanness><Lens dislocation><Lung Diseases><Lysyl Oxidase><Marfan Syndrome><Materials Testing><Measures><Mechanics><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><Myopia><Nearsightedness><Null Mouse><Ocular Tension><Optics><Pathology><Patients><Pb element><Phenotype><Physiologic Intraocular Pressure><Play><Proliferating><Property><Protein-Lysine 6-Oxidase><Proteins><Proteome><Pulmonary Diseases><Pulmonary Disorder><Retinal Detachment><Role><Rupture><S Period><S phase><Scanning Force Microscopy><Shapes><Skin Diseases><Skin Diseases and Manifestations><Staining method><Stains><Structure><Surface><Synthesis Period><Synthesis Phase><System><Techniques><Tensile Strength><Testing><Thinness><Tissue Growth><Transmission><Visualization><Weill-Marchesani syndrome><ages><biologic><biomechanical><cataractogenesis><cataractous lenses><crosslink><cutaneous disease><dermal disease><dermal disorder><developmental><disease of the lung><disorder of the lung><extracellular><eye disorder><fibrillin-1><gene null><genome mutation><glaucomatous><heavy metal Pb><heavy metal lead><human model><imaging><insight><intra-ocular pressure><lens><lenses><lung disorder><mechanic><mechanical><mechanical stimulus><model of human><molecular biomarker><molecular marker><mouse model><murine model><mutant><near vision><null mutation><ocular disease><ocular disorder><ontogeny><ophthalmopathy><optical><postnatal><pressure><response><retina detachment><skin disorder><social role><spatial relationship><three dimensional><three dimensional structure><transmission process><vascular><viscoelasticity>