The most common inherited human disorder causing blindness is retinitis pigmentosa, and the most common cause of blindness in persons over the age of 60 is age-related macular degeneration. Blindness in both families of diseases is caused by photoreceptor (PR) cell death. At present, no widely accepted form of therapy exists for these diseases. The long-term objectives of our research program are 1) to elucidate the cellular and genetic mechanisms that lead to PR cell death, and 2) to develop therapeutic means to delay or prevent PR degeneration in hereditary, age-related and environmentally induced retinal degenerations (RDs). One cellular mechanism that may have an important role in PR cell death and offer therapeutic possibilities in RDs is the Unfolded Protein Response (UPR). As proteins are assembled in the endoplasmic reticulum (ER), they must be properly folded to leave the ER. It has long been known that the most common form of autosomal dominant retinitis pigmentosa in the United States is caused by the P23H mutation, and that this mutant protein is misfolded leading to its retention within the ER. Misfolded proteins generate ER stress and activate the UPR signaling pathways. The UPR then upregulates genes that increase the ER's protein folding capacity. If homeostasis cannot be restored, UPR signaling eventually induces cell death by apoptosis. We found that three parallel branches of the UPR, governed by IRE1, ATF6 and PERK, behave significantly differently in time course and that these differences in the duration of their signaling may provide the switch that influences the cell's ultimate fate in response to ER stress. For example, CHOP, a transcription factor induced by the PERK branch of the UPR is sustained and promotes cell death. By contrast, the IRE1 pathway appears to be cytoprotective, and its attenuation is part of the "cell death switch," as sustaining IRE1 signaling in the face of persistent ER stress can result in significantly enhanced cell survival. Thus, modulation of the UPR offers a possible new avenue for therapy for at least some RDs. There are many RDs that do not appear to result from misfolded proteins, so it is important to know how universal ER stress and UPR signaling are in RDs. We propose to examine this in a number of RDs in native RD models, gene ablation models, as well as by alteration of PR cell death timing by mutant gene dose, environmental manipulation, or modifier genes. Moreover, we will examine the potential therapeutic role of UPR modulation through gene-based methods, to seek combinational therapy with UPR modulation and neuroprotection, and to attempt to develop transgenic mice that would allow real-time, noninvasive assessment of ER stress/UPR signaling in PRs, which would be extremely useful for RD therapeutic research.

Public Health Relevance

More than 6 million people in the United States have blinding diseases with no known cure that result from the death of photoreceptor cells in the eye. The goals of this research program are to study many aspects of one cellular mechanism known as the Unfolded Protein Response that may have an important role in photoreceptor cell death and offer therapeutic possibilities for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY001919-35
Application #
8197257
Study Section
Special Emphasis Panel (ZRG1-CB-G (02))
Program Officer
Shen, Grace L
Project Start
1978-07-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
35
Fiscal Year
2012
Total Cost
$577,521
Indirect Cost
$170,334
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kroeger, Heike; LaVail, Matthew M; Lin, Jonathan H (2014) Endoplasmic reticulum stress in vertebrate mutant rhodopsin models of retinal degeneration. Adv Exp Med Biol 801:585-92
Ghosh, Rajarshi; Wang, Likun; Wang, Eric S et al. (2014) Allosteric inhibition of the IRE1? RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534-48
Hiramatsu, Nobuhiko; Messah, Carissa; Han, Jaeseok et al. (2014) Translational and posttranslational regulation of XIAP by eIF2? and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol Biol Cell 25:1411-20
Li, Mei; Yasumura, Douglas; Ma, Aye Aye K et al. (2013) Intravitreal administration of HA-1077, a ROCK inhibitor, improves retinal function in a mouse model of huntington disease. PLoS One 8:e56026
Gorbatyuk, Marina S; Gorbatyuk, Oleg S; LaVail, Matthew M et al. (2012) Functional rescue of P23H rhodopsin photoreceptors by gene delivery. Adv Exp Med Biol 723:191-7
Wen, Rong; Tao, Weng; Luo, Lingyu et al. (2012) Regeneration of cone outer segments induced by CNTF. Adv Exp Med Biol 723:93-9
Zhao, Chen; Yasumura, Douglas; Li, Xiyan et al. (2011) mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J Clin Invest 121:369-83
Maddox, Dennis M; Hicks, Wanda L; Vollrath, Douglas et al. (2011) An ENU-induced mutation in the Mertk gene (Mertknmf12) leads to a slow form of retinal degeneration. Invest Ophthalmol Vis Sci 52:4703-9
Lin, Jonathan H; Lavail, Matthew M (2010) Misfolded proteins and retinal dystrophies. Adv Exp Med Biol 664:115-21
Li, Yiwen; Tao, Weng; Luo, Lingyu et al. (2010) CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PLoS One 5:e9495

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