The mechanisms that specify the size and shape of the lens are unknown. We have combined cell biological experiments with mathematical modeling to gain insights into the lens growth process. Modeling suggests that compaction of cells in the lens interior must occur if the lens is not to overgrow the eye. In the mouse, compaction begins in the third postnatal week and is largely completed by the sixth, providing an opportunity to examine both the cause and consequence of the process.
In Aim 1, therefore, we will examine the process of fiber cell compaction and determine how it relates to the formation of the internal refractive index gradient of the lens. We will test whether compaction is due to the redistribution of water in response to an oncotic pressure differential established between the inner and outer cell layers. In response to the cumulative push provided by cell division at higher latitudes, epithelial cells flow towards the lens equator, dividing multiple times en route and forming clusters of clonally-related cells. We hypothesize that this process constitutes the means by which somatic mutations generated in sun-exposed regions of the epithelium could be amplified and conveyed into the fiber cell mass.
In Aim 2, we will use error-corrected sequencing to test the hypothesis that human lens epithelial cells harbor low frequency somatic mutations in genes essential for lens transparency. We will also test whether the syncytial organization of the lens tissue affects the manner in which somatic mutations manifest in the fiber cell compartment. Finally, we will port our growth model to the human lens, developing the necessary mathematical framework to model the spatial behavior of individual cells (and their lineages) over time. In conjunction with the sequencing experiments, this will allow us to predict the impact on lens transparency of mutations occurring in individual epithelial cells at specific locations on the lens surface and at various points in the lifespan.
Unlike most organ systems, the eye lens grows throughout life. The growth process influences the optical performance of the lens and the development, later in life, of presbyopia and cataracts. The experiments described in this proposal will provide insights into the biology of the healthy lens and the underlying causes of cataracts, the leading cause of blindness globally.
| De Maria, Alicia; Zhao, Haiqing; Bassnett, Steven (2018) Expression of potassium-dependent sodium-calcium exchanger in the murine lens. Exp Eye Res 167:18-24 |
| Bassnett, Steven; Costello, M Joseph (2017) The cause and consequence of fiber cell compaction in the vertebrate lens. Exp Eye Res 156:50-57 |
| Šiki?, Hrvoje; Shi, Yanrong; Lubura, Snježana et al. (2017) A full lifespan model of vertebrate lens growth. R Soc Open Sci 4:160695 |
| Bassnett, Steven; Šiki?, Hrvoje (2017) The lens growth process. Prog Retin Eye Res 60:181-200 |
| Mesa, Rosana; Tyagi, Manoj; Harocopos, George et al. (2016) Somatic Variants in the Human Lens Epithelium: A Preliminary Assessment. Invest Ophthalmol Vis Sci 57:4063-75 |
| De Maria, Alicia; Bassnett, Steven (2015) Birc7: A Late Fiber Gene of the Crystalline Lens. Invest Ophthalmol Vis Sci 56:4823-34 |
| Šiki?, Hrvoje; Shi, Yanrong; Lubura, Snježana et al. (2015) A stochastic model of eye lens growth. J Theor Biol 376:15-31 |
| Shi, Yanrong; De Maria, Alicia; Lubura, Snježana et al. (2015) The penny pusher: a cellular model of lens growth. Invest Ophthalmol Vis Sci 56:799-809 |
| Shi, Yanrong; Tu, Yidong; Mecham, Robert P et al. (2013) Ocular phenotype of Fbn2-null mice. Invest Ophthalmol Vis Sci 54:7163-73 |
| Mesa, Rosana; Bassnett, Steven (2013) UV-B-induced DNA damage and repair in the mouse lens. Invest Ophthalmol Vis Sci 54:6789-97 |
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