Cataract disease, the leading cause of blindness worldwide, is the end result of increased scattering of light within the human ocular lens. The proposed research seeks to establish the multi-component phase diagram of concentrated, aqueous eye lens crystallin protein mixtures, together with its statistical-thermodynamic molecular basis. Neutron scattering, X-ray scattering, light scattering and statistical thermodynamic modeling and computer simulation will be used (i) to establish the phase diagram and light scattering of concentrated mixtures of gamma crystallins with alphaA crystallin, alphaB crystallin and alphaAB mixtures, (ii) to measure, with small angle neutron scattering, the crystallin- specific liquid structure of selectively deuterated gamma and alpha crystallins in highly concentrated mixtures, (iii) to evaluate the influence of gamma crystallin charge on the phase boundary locations, the light scattering intensity, the virial coefficients and the liquid structure (iv) to establish the virial coefficients, interactions and liquid structure of dilute and concentrated alphaA and alphaB crystallin solutions and their mixtures. These steps are essential elements for providing a sound molecular understanding of the phase diagram of concentrated mixtures of gamma and alpha crystallin, and as such bear on the molecular underpinnings of cataract. Cataract disease, the leading cause of blindness worldwide, is the end result of increased scattering of light within the human ocular lens. The proposed research seeks to further investigate the molecular origins of one potential source of this light scattering, a change of phase of the eye lens proteins that has long been known to be driven by protein-protein attractions. The lens of the eye contains a mixture of proteins, however, and this phase transition is now being understood to result not only from protein-protein attractions, but also from differences in size and other properties between the proteins.
This research aims to help quantify how various differences in protein properties lead to light scattering. This will be done by varying protein size and charge deliberately, by using special short-wavelength scattering techniques that can help find out which types of protein molecules are next to one another on average, and by investigating the role in the phase transition of certain lens proteins important in cataract, alpha-A and alpha-B crystallin. By finding the detailed molecular origins of the normal and the diseased state of the eye lens, a sound basis for ameliorating cataract can potentially be constructed, providing society with the possible benefits of one longer lasting aspect of health. Further, by elucidating the principles governing the crowded interior of the eye lens cells, principles that bear more generally on the crowded interiors of living cells stand to be discovered, principles that may have very broad impact. ? ? ?
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