Every person beyond the age of 50 experiences severe decline of accommodation, leading to presbyopia, withnegative consequences in terms of quality of life and work performance. The age-related stiffening of the lensis believed to play a primary role in the decrease of accommodation power. However, currently availableexperimental data on lens's elastic modulus, its age progression and, importantly, the spatial distribution ofelastic modulus inside the lens are highly variable. As a result, a definitive explanation of the biophysicalprinciples guiding lens accommodation is still missing, which has generated controversial explanation andhindered the development of effective approaches to delay/slow down presbyopia onset or restoreaccommodation power. To overcome this limitation, the applicants have developed an optical technology,Brillouin microscopy, which can map the spatial distribution of the lens elastic modulus non-perturbatively andwith 3D micron resolution. Leveraging on this novel technology, the objective of this proposal is to measure the3D biomechanical properties of the aging lens and understand the biophysical principles governingaccommodation. The central hypothesis of the proposal is that the accommodation power is lost as a result ofan age-related variation in the spatial distribution of the local modulus inside the lens, which results in overallincrease of lens stiffness. The hypothesis stems from preliminary data collected with ex vivo and in vivo humanlens samples.
In Aim 1, the hypothesis will be tested through a systematic comparison of elasticity-basedmetrics of lenses of different ages and their corresponding accommodation power. The statistical analysis ofthese data will verify that metrics that account for the spatial distribution of modulus are better predictors ofaccommodation than the local values of elastic moduli inside the lens.
In Aim 2, the hypothesis will be testedby experimentally validating the predictions of a biophysical lens model, developed by the applicants, wherethe lens behaves as a composite ellipsoid with increasing viscoelastic modulus from periphery to nucleus. Withage, the spatial elasticity gradient and the relative thickness of the harder region inside the lens increase. Thisresults in increased lens stiffness causing the decline of accommodation power. As the applicants havedemonstrated that Brillouin technology can be translated to clinical use, the results of this research can bevalidated in vivo. The approach is innovative because it introduces non-invasive 3D-resolved measurements oflens elastic properties and first-principle biophysical modeling. The research is significant because, byunveiling the crucial role of the spatial distribution of elastic modulus inside the lens, it is expected to verticallyadvance the mechanistic understanding of the accommodation process as well as of lens growth and function.Ultimately, the knowledge gained from this research is likely to inspire and facilitate and accelerate the on-going effort to develop pharmacological or surgical interventions to preserve or restore accommodation power.
This proposal is relevant to the public health because it will elucidate the governing principles of theaccommodation process and identify the mechanical properties of the crystalline lens that drive the decline ofaccommodation power leading to presbyopia. This is expected to inspire; develop and enable testing currentand future approaches to preserve or restore accommodation. In addition; this will broadly provide mechanisticinsights on lens growth and function as well as on cataract formation. Therefore; the proposed research isrelevant to the NIH's mission of pursuing fundamental knowledge in order to extend healthy life.!
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