Usha P. Andley, Ph.D.

Ophthalmology and Visual Sciences
Biochemistry and Molecular Biophysics

Biochemistry, Biophysics, and Structural Biology Program
Molecular Cell Biology Program

  • 314-362-7167

  • 314-362-5891

  • 314-362-3638

  • 8096

  • 1114 C McMillan Building


  • aging, protein structure, cell cycle, proteomics, cataract

  • Small heat shock protein functions in ocular systems and stress

Research Abstract:

Cataracts are the result of the loss of transparency and opacification of the eye lens, and are responsible for 51% of blindness worldwide, which represents >20 million people. Cataracts are primarily a disease of aging. My laboratory studies the biochemical basis of cataract formation. We are using several approaches to understand the mechanisms by which lens crystallins undergo misfolding and high molecular weight protein aggregation that occurs in a majority of human cataracts. Short-range order of lens crystallins in lens fiber cells helps to maintain the lens in a transparent state. Lens proteins do not turn over for the entire life of an individual, and must be kept in a native conformation in order for the lens to remain transparent. One of the major proteins of the lens is alpha-crystallin, which belongs to the small heat shock protein family of molecular chaperones. This protein, composed of two gene products alpha A and alpha B-crystallins, plays important roles in the lens and other tissues. Our recent work showed that lens epithelial cultures of alpha A knockout mice have slower growth and an altered cell cycle distribution, and these findings may explain why the alpha A null lenses are smaller than controls. In contrast, lens epithelial cells derived from alpha B null mice transform at a higher rate and demonstrate increased proliferation and genomic instability. These new findings indicate that alpha A and alpha B have important cellular roles not previously recognized. We have demonstrated that expression of alpha-crystallin protein in lens epithelial cells confers a protective phenotype. Mutations in crystallin genes form the basis of several hereditary cataracts. Knock-in mice expressing mutations associated with human hereditary cataracts are the focus of our present research. The influence of cataract on autophagy and the unfolded protein response will be important to understand the role of protein degradation of misfolded proteins in human cataract formation. These studies will enhance the understanding of cataract development and progression in animal models, which can be correlated with human cataract development. Using knock-in and knock-out mouse models for cataracts, we have recently identified the likely in vivo substrates of alpha crystallin in the lens using proteomic techniques. In a major new endeavor, we are testing novel small molecule pharmaceutical compounds to reverse and delay cataract development using animal models generated in our laboratory.

Selected Publications:

Andley UP, Goldman JW. Autophagy and UPR in alpha-crystallin mutant knock-in mouse models of hereditary cataracts. Biochim. Biophys. Acta 2016; 1860 (1 Pt B): 234-239.

Makley LN, McMenimen KA, DeVree BT, Goldman JW, McGlasson BN, Rajagopal P, Dunyak BM, McQuade TJ,Thompson AD, Sunahara R, Klevit RE, Andley UP, Gestwicki JE. Pharmacological chaperone for α-crystallin partially restores transparency in cataract models. Science 2015; 350 (6261): 674-677.

Andley UP, Malone JP, Townsend RR. In vivo substrates of lens molecular chaperones αA-crystallin and αB-crystallin. PLoS One. 2014; 9(4): e95507.

Andley UP, Malone J, Hamilton PD, Ravi N, Townsend RR. Comparative proteomic analysis identifies increases in the abundance of βB2- crystallin and vimentin after the deletion of the small heat shock proteins αA- and αB-crystallins. Biochemistry. 2013; 52, 2933-2948.

Wignes JA, Goldman JW, Weihl CC, Bartley MG, Andley UP. P62 expression and autophagy in αB-crystallin R120G mutant knockin mouse model of hereditary cataract. Exp Eye Res. 2013; 115, 263-273.

Last Updated: 1/13/2016 3:08:06 PM

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