Abstract

Circadian clocks control fundamental pathways in the retina, such as photoreceptor outer segment turnover. This has led to the suggestion that altered circadian regulation could contribute to age related macular degeneration (AMD) and other retinal diseases. However, this suggestion has never been tested. This proposal addresses the question of retinal circadian organization through use of targeted mutations in three """"""""central clock genes"""""""" (Per1, Per2, and Per3) and one clock-regulated gene (mNoc). Mice lacking all 3 Pers are expected to lack endogenous clock activity, while the single Per or mNoc deletions are expected to partially disrupt retinal circadian output.
Specific Aim 1 tests the hypothesis that targeted mutations in Per1, Per2, Per3, and mNoc (or their combinations) will cause functional deficits that lead to photoreceptor loss.
Specific Aim 2 analyzes alterations in previously characterized retinal circadian rhythms in Per- and mNoc-deficient mice to identify clock-regulated pathways relevant to photoreceptor health.
Specific Aim 3 tests the hypothesis that the mouse retina contains multiple clock systems that include photoreceptors, dopaminergic amacrine cells, retinal pigment epithelial cells by analyzing circadian expression of central clock genes. This project fills specific gaps in our knowledge of retinal circadian organization at the cellular level in a mammalian system, and assesses the potential effects of circadian gene disruption on retinal health.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002414-31
Application #
7051980
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
1989-07-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
31
Fiscal Year
2006
Total Cost
$369,849
Indirect Cost

  Institution

Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226

  Publications

Besharse, Joseph C; McMahon, Douglas G (2016) The Retina and Other Light-sensitive Ocular Clocks. J Biol Rhythms 31:223-43
Carver, Koryn A; Lourim, David; Tryba, Andrew K et al. (2014) Rhythmic expression of cytochrome P450 epoxygenases CYP4x1 and CYP2c11 in the rat brain and vasculature. Am J Physiol Cell Physiol 307:C989-98
Fogerty, Joseph; Besharse, Joseph C (2014) Subretinal infiltration of monocyte derived cells and complement misregulation in mice with AMD-like pathology. Adv Exp Med Biol 801:355-63
Toonen, Joseph; Liang, Lina; Sidjanin, Duska J (2012) Waved with open eyelids 2 (woe2) is a novel spontaneous mouse mutation in the protein phosphatase 1, regulatory (inhibitor) subunit 13 like (Ppp1r13l) gene. BMC Genet 13:76
Scoma, Heather Dehlin; Humby, Monica; Yadav, Geetha et al. (2011) The de-ubiquitinylating enzyme, USP2, is associated with the circadian clockwork and regulates its sensitivity to light. PLoS One 6:e25382
Fogerty, Joseph; Besharse, Joseph C (2011) 174delG mutation in mouse MFRP causes photoreceptor degeneration and RPE atrophy. Invest Ophthalmol Vis Sci 52:7256-66
Insinna, Christine; Luby-Phelps, Katherine; Link, Brian A et al. (2009) Analysis of IFT kinesins in developing zebrafish cone photoreceptor sensory cilia. Methods Cell Biol 93:219-34
Insinna, Christine; Humby, Monica; Sedmak, Tina et al. (2009) Different roles for KIF17 and kinesin II in photoreceptor development and maintenance. Dev Dyn 238:2211-22
Insinna, Christine; Besharse, Joseph C (2008) Intraflagellar transport and the sensory outer segment of vertebrate photoreceptors. Dev Dyn 237:1982-92
Green, Carla B; Douris, Nicholas; Kojima, Shihoko et al. (2007) Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proc Natl Acad Sci U S A 104:9888-93

Showing the most recent 10 out of 52 publications