Integrating cell sorting and tissue shaping mechanisms during cornea maturation

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DESCRIPTION (provided by applicant): Corneal ectasia, a warping and thinning of the anterior eye, afflicts 1 in 2000 of the general population. Its dynamic mechanism remains poorly understood, in part, due to its diverse and pleiotropic environmental and genetic causes. While treatment options are available to most, such methods primarily act as near-term patches that can lead to worsened progressive regression, which typically appears two years later. Therefore, a primary challenge is to better understand the long-term visco-elastic response in degenerative conditions and after treatment. Diverse paradigms are being developed in which investigators are focusing on characterizing disease susceptibility, quantifying measures for diagnoses, characterizing wound-healing/fibrotic behaviors, designing artificial materials and isolating stem/progenitor cells for replacement, and affecting material properties through modeling of biomechanical parameters that can affect corneal structure. We are developing a concurrent model of vertebrate cornea maturation using a combination of experiment, imaging and computation. Our studies focus on understanding a peculiar spiral segregation behavior that operates in mammalian corneas. The behavior has been observed across the corneal surface, in epithelial cells and migrating neural extensions. Importantly, it is disrupted in patients with keratoconus, an ectatic condition. These observations suggest the existence of a common force driving cell segregation and tissue shaping. We propose to develop an ensemble metric to quantify the rate of spiral emergence using three different vertebrate model organisms. The development of a specific fractal signature serves as a classification scheme and has the potential to complement discrete measures by which to diagnose subclinical keratoconus. To address a need to interrogate biomechanical parameters that affect corneal curvature, we will utilize modern advancements in both genetic and biomedical technologies to examine the role of microtubules in affecting epithelial cell segregation behaviors. Our proposal seeks to develop a platform upon which to integrate the epithelial layer with existing stromal models to better understand the integration of systemic networks that affect refractive regression and the adaptive response. PUBLIC HEALTH RELEVANCE: A primary problem with diagnosis and treatment of ecstatic eye disease, which is a warping and thinning of the cornea, is our lack of understanding of the factors that contribute to its long-term regression, a gradual change in shape. We are developing a quantitative, concurrent, executable model of vertebrate cornea maturation that seeks to determine whether intracellular motion exerted by epithelial cells can affect this process. We hope such explicit treatment of the corneal epithelium as an integrated network with the rest of the anterior chamber will lead to better virtual models of the human eye, which can support development of novel therapeutics and subclinical diagnoses.