Transparency is the fundamental structural feature that distinguishes lens cells from all other mammalian cells. In lens cells, transparency is established when spatial fluctuations in cytoplasmic density become small relative to the wavelength of light, which minimizes light scattering. The size of the spatial fluctuations depends on molecular interactions between cytoplasmic constituents of lens cells. Changes in these molecular interactions can produce loss of transparency and formation of cataracts. The present application is a continuation of studies on development and maintenance of lens transparency. The previous proposal began studies on development of lens transparency, identified reversible stages of lens opacification and discovered completely new reagents for preventing opacification in rats exposed to Irradiation. The present application proposes continued research on development of transparency to characterize molecular interactions responsible for normal development and maintenance of lens transparency in vivo. and to test the new reagents on several cataract models: galactosemic, selenite, streptozotocin and R.C.S. (Royal College of Surgeons rat) In the proposed research plan, the studies will (1) evaluate quantitatively the spatial fluctuations in lens cytoplasm during normal development of transparency in embryonic lens cells; (2) characterize the molecular interactions responsible for normal spatial fluctuations in transparent lens cells, and (3) demonstrate the effectiveness of new phase separation inhibitors on the prevention of cataracts in vivo. The working hypothesis is that direct analysis of the spatial fluctuations in lens cells during development will lead to an understanding of molecular interactions that regulate transparent cell structure.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY004542-08
Application #
3258961
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1982-06-01
Project End
1993-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
8
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Clark, John I (2016) Functional sequences in human alphaB crystallin. Biochim Biophys Acta 1860:240-5
Anderson, David M G; Floyd, Kyle A; Barnes, Stephen et al. (2015) A method to prevent protein delocalization in imaging mass spectrometry of non-adherent tissues: application to small vertebrate lens imaging. Anal Bioanal Chem 407:2311-20
Clark, John I (2013) Self-assembly of protein aggregates in ageing disorders: the lens and cataract model. Philos Trans R Soc Lond B Biol Sci 368:20120104
Gokhin, David S; Nowak, Roberta B; Kim, Nancy E et al. (2012) Tmod1 and CP49 synergize to control the fiber cell geometry, transparency, and mechanical stiffness of the mouse lens. PLoS One 7:e48734
Clark, Tyler J W; Houck, Scott A; Clark, John I (2012) Hemoglobin interactions with ?B crystallin: a direct test of sensitivity to protein instability. PLoS One 7:e40486
Greiling, Teri M S; Clark, John I (2012) New insights into the mechanism of lens development using zebra fish. Int Rev Cell Mol Biol 296:1-61
Qu, Bo; Landsbury, Andrew; Schönthaler, Helia Berrit et al. (2012) Evolution of the vertebrate beaded filament protein, Bfsp2; comparing the in vitro assembly properties of a ""tailed"" zebrafish Bfsp2 to its ""tailless"" human orthologue. Exp Eye Res 94:192-202
Houck, Scott A; Landsbury, Andrew; Clark, John I et al. (2011) Multiple sites in ?B-crystallin modulate its interactions with desmin filaments assembled in vitro. PLoS One 6:e25859
Houck, Scott A; Clark, John I (2010) Dynamic subunit exchange and the regulation of microtubule assembly by the stress response protein human alphaB crystallin. PLoS One 5:e11795
Greiling, Teri M S; Aose, Masamoto; Clark, John I (2010) Cell fate and differentiation of the developing ocular lens. Invest Ophthalmol Vis Sci 51:1540-6

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