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Principal Investigator: Jeffrey W Ruberti
Organization: NORTHEASTERN UNIVERSITY
Fiscal Year: 2024
Award: $505,592
Funding agency: National Eye Institute
Project Summary
The cornea and sclera are the principal load bearing members in the tough fibrous ocular tunic which we consider
to be an integrated mechano-biological structure. During development, the shape of the eye has been tuned to
conform to a specific mechanical environment through a long time-scale integration of its loading history with
its initial genetic patterning. Although mechanics are known to contribute to the development of many
connective tissues, the ocular globe is particularly sensitive to pressure (tensile wall stress) during the expansive
phase of growth. Even in the mature ocular tunic, mechanical instabilities often manifest as conditions which
disrupt vision (e.g. myopia, keratoconus, post-LASIK ectasia, tractional retinal detachments and glaucoma).
While the underlying causes of tissue structural instabilities are poorly understood, we suspect that they are
mechanobiological in nature and potentially reflect an imbalance in the tensional homeostasis that exists
between mesenchymal cells, their local ECM and the global mechanical environment. We know that during
development, disruption of the mechanical connection between fibroblastic cells and their ECM severely retards
ocular growth in a manner analogous to pressure loss, suggesting that mechanical communication is critical to
proper ocular morphogenesis. However, the effect of mechanical forces on the mechanisms which drive tissue
formation and growth are not well characterized. It is remarkable that we still do not fully understand how the
most important structural molecule in vertebrates, collagen, is efficiently assembled into highly-organized,
functional, load-bearing tissues which are massively expanded into macroscale structures during growth.
However, if we are able to uncover new mechanisms which control tissue formation and growth, we will have
access to information which can inform therapies for a variety of pathological conditions including fibrosis,
myopia, keratoconus and potentially, glaucoma. Additionally, if we understand how tissue is produced, then
there will be implications for engineering corneas de novo and for improving approaches to regenerative corneal
medicine. In the proposed work, we plan combine our human cell culture model of corneal stromal tissue
elaboration with live-cell mechanodynamics imaging to directly observe single collagen molecules during their
transition from solution to fibrils. We will thus directly test a new hypothesis which directly couples local and
globally applied forces directly to molecular assembly of collagen during fibrillogenesis and growth. The working
hypothesis for this proposal is that force causes corneal stromal ECM elaboration to regulate fibril assembly,
remodeling and growth. If the hypothesis is correct, there are myriad mechanotherapeutic opportunities and
more critically, our basic understanding of collagenous tissue formation and growth, will be fundamentally
altered.
Terms: <Acceleration><Access to Information><Address><Animals><Autoregulation><Biopolymers><Body Tissues><Causality><Cell Body><Cell Culture Techniques><Cell-Extracellular Matrix><Cells><Cicatrix><Cold-Insoluble Globulins><Collagen><Collagen Fibril><Communication><Connective Tissue><Cornea><Corneal Stroma><Coupled><Couples><Custom><Deposit><Deposition><Development><Diffusion><ECM><Ectasia><Engineering><Environment><Etiology><Event><Exclusion><Experimental Designs><Extracellular Matrix><Eye><Eyeball><FN1><Fibroblasts><Fibronectin 1><Fibronectins><Fibrosis><Generalized Growth><Genetic><Glaucoma><Goals><Growth><History><Homeostasis><Human><Image><In Vitro><Integrins><Integrins Extracellular Matrix><Intervertebral Disk><Intervertebral disc structure><Investigation><Keratoconus><Knowledge><LASIK><LETS Proteins><Large External Transformation-Sensitive Protein><Laser In Situ Keratomileusis><Laser Intrastromal Keratomileuses><Laser Intrastromal Keratomileusis><Laser-Assisted Stromal In Situ Keratomileusis><Length><Ligaments><Load Bearing><Measurement><Measures><Mechanics><Medicine><Mesenchymal><Methods><Microscopy><Minor><Modeling><Modern Man><Molecular><Morphogenesis><Myofibroblast><Myopia><Natural regeneration><Nature><Nearsightedness><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Organization Charts><Pathologic><Pathologic Dilatation><Pathological Dilatation><Pattern><Phase><Physiological Homeostasis><Position><Positioning Attribute><Production><Recording of previous events><Regeneration><Retinal Detachment><Role><Scars><Sclera><Shapes><Sight><Speed><Stress><Structure><Tendon structure><Tendons><Testing><Tissue Engineering><Tissue Growth><Tissues><Traction><Tunic><Vertebrate Animals><Vertebrates><Vision><Weight Bearing><Weight-Bearing state><White of Eye><Work><Wound Repair><alpha 2-Surface Binding Glycoprotein><bioengineered tissue><blebbistatin><causation><cell culture><cell cultures><cicatrix corneal><corneal><corneal fibrosis><corneal scar><customs><developmental><diffused><diffuses><diffusing><diffusions><disease causation><engineered tissue><fibrillogenesis><glaucomatous><histories><imaging><improved><light transmission><live cell microscopy><mechanic><mechanical><mechanical cue><mechanical force><mechanical signal><member><molecular assembly><molecular assembly/self assembly><molecular self assembly><monomer><morphogenetic process><near vision><ontogeny><organizational structure><outreach to information><pressure><prospective><regenerate><regenerative><response><retina detachment><single molecule><social role><temporal measurement><temporal resolution><theories><time measurement><tool><vertebrata><visual function><wound healing><wound recovery><wound resolution>