This application is in response to potential support for two years as part of the American Recovery and Reinvestment Act of 2009.
The Specific Aims have been modified from the original proposal to fit 2 years of funding. The proteasome complex plays a fundamental role in processes essential for cell viability, such as cell cycle regulation, control of signal transduction and gene expression, and the degradation of oxidized and misfolded proteins. Two types of proteasomes, the constitutive and immunoproteasomes, have been described. The proposed work investigates factors that influence the balance between the two proteasome subtypes in cells of the retina, and tests specific hypotheses regarding the dependence of retinal homeostasis on immunoproteasome function. The underlying hypothesis is that immunoproteasome performs functions that are vital to cells under stress;this hypothesis links the immunoproteasome to the innate immune system, and its role in tissue homeostasis, but does not limit it to immunological functions.
Aim 1 tests the hypothesis that immunoproteasome is critical for maintaining a healthy retina under normal conditions in vivo. The approach is to use immunoproteasome-deficient mice lacking two (lmp7/-/mecl-r/-) catalytic subunits of immunoproteasome (L7Ml mice) to determine the consequences of inhibiting immunoproteasome expression by comparing age-matched WT and L7Ml mice, ages 1 to 24 months.
Aim 2 tests the hypothesis that the inability to make immunoproteasome sensitizes the retina to more adverse outcomes following extraordinary stress. The extent of damage in WT and L7Ml mice after two distinct types of injury models (constant light and optic nerve crush) will be tested. Results from these experiments will help verify that immunoproteasome is an essential component of the retinal stress response and plays a fundamental role in maintaining retinal health.
The proteasome mediates a large percentage of cellular protein degradation, such as cell-cycle regulation, signal transduction, and protein quality control. Dysregulation of proteasome- dependent proteolysis has been linked to a growing number of neurodegenerative diseases (i.e., Parkinson's and Alzheimer's Diseases) and cancer. A comprehensive understanding of proteasome regulation in health and disease is requisite for development of effective therapeutic interventions.
| Kapphahn, Rebecca J; Richards, Michael J; Ferrington, Deborah A et al. (2018) Lipid-derived and other oxidative modifications of retinal proteins in a rat model of Smith-Lemli-Opitz syndrome. Exp Eye Res : |
| Schuld, Nathan J; Hussong, Stacy A; Kapphahn, Rebecca J et al. (2015) Immunoproteasome deficiency protects in the retina after optic nerve crush. PLoS One 10:e0126768 |
| Maldonado, Marcela; Kapphahn, Rebecca J; Terluk, Marcia R et al. (2013) Immunoproteasome deficiency modifies the alternative pathway of NF?B signaling. PLoS One 8:e56187 |
| Ferrington, Deborah A; Roehrich, Heidi; Chang, Angela A et al. (2013) Corneal wound healing is compromised by immunoproteasome deficiency. PLoS One 8:e54347 |
| Ferrington, Deborah A; Gregerson, Dale S (2012) Immunoproteasomes: structure, function, and antigen presentation. Prog Mol Biol Transl Sci 109:75-112 |
| Hussong, Stacy A; Roehrich, Heidi; Kapphahn, Rebecca J et al. (2011) A novel role for the immunoproteasome in retinal function. Invest Ophthalmol Vis Sci 52:714-23 |
| Hussong, Stacy A; Kapphahn, Rebecca J; Phillips, Stacia L et al. (2010) Immunoproteasome deficiency alters retinal proteasome's response to stress. J Neurochem 113:1481-90 |
| Balog, Edward M; Lockamy, Elizabeth L; Thomas, David D et al. (2009) Site-specific methionine oxidation initiates calmodulin degradation by the 20S proteasome. Biochemistry 48:3005-16 |
| Ferrington, Deborah A; Hussong, Stacy A; Roehrich, Heidi et al. (2008) Immunoproteasome responds to injury in the retina and brain. J Neurochem 106:158-69 |
| Kapphahn, Rebecca J; Bigelow, Erin J; Ferrington, Deborah A (2007) Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina. Exp Eye Res 84:646-54 |
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