The most common cause of inherited blindness is retinitis pigmentosa, a family of diseases with various forms of inheritance caused by mutations in more than 45 genes. The rhodopsin gene has more than 100 distinct mutations, and many forms of autosomal dominant retinitis pigmentosa (adRP) involve abnormal rhodopsin folding in which the misfolded protein is retained in the endoplasmic reticulum. However, it is not known how misfolded rhodopsin leads to the photoreceptor degeneration seen in the disease. The unfolded protein response (UPR) comprises a set of cellular signaling pathways present in all mammalian cells that detects misfolded proteins in the endoplasmic reticulum and directs protective and apoptotic actions taken by the cell. UPR signaling acts cytoprotectively by elevating chaperone levels; elevating ubiquitin-proteasome system activity; and reducing protein translation, all of which cumulatively decrease misfolded protein levels. UPR signaling can also trigger apoptosis through mitochondrial-dependent cytochrome C release and downstream activation of caspase-dependent protease cascades. This proposal investigates the role of UPR signaling in the pathogenesis of adRP using tissue culture systems and transgenic animal models of P23H-rhodopsin adRP. Specifically, this project aims to: 1) Determine the mechanism by which the photoreceptor senses misfolded rhodopsin, 2) Determine how rhodopsin misfolding lead to apoptosis, and 3) Test if modulation of the UPR can prevent misfolded rhodopsin-induced cell death. Dr. Jonathan Lin, the principal investigator, is an M.D., Ph.D., who received his graduate degree in neuroscience, completed his residency training in anatomic pathology, and wishes to develop the skills necessary to become an independent physician-scientist. The sponsor, Dr. Peter Walter, discovered the Unfolded Protein Response and has a strong record of training successful physician-scientist investigators. The co-sponsor, Dr. Matthew LaVail, is an expert in vision biology and retinal degeneration, and created and characterized the P23H-rhodopsin transgenic rat models of adRP. ? ? ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
Clinical Investigator Award (CIA) (K08)
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Study Section
Special Emphasis Panel (ZEY1-VSN (02))
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Neuhold, Lisa
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Kroeger, Heike; Messah, Carissa; Ahern, Kelly et al. (2012) Induction of endoplasmic reticulum stress genes, BiP and chop, in genetic and environmental models of retinal degeneration. Invest Ophthalmol Vis Sci 53:7590-9
Chiang, Wei-Chieh; Messah, Carissa; Lin, Jonathan H (2012) IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin. Mol Biol Cell 23:758-70
Kroeger, Heike; Chiang, Wei-Chieh; Lin, Jonathan H (2012) Endoplasmic reticulum-associated degradation (ERAD) of misfolded glycoproteins and mutant P23H rhodopsin in photoreceptor cells. Adv Exp Med Biol 723:559-65
Chiang, Wei-Chieh; Hiramatsu, Nobuhiko; Messah, Carissa et al. (2012) Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulation. Invest Ophthalmol Vis Sci 53:7159-66
Shinde, Vishal M; Sizova, Olga S; Lin, Jonathan H et al. (2012) ER stress in retinal degeneration in S334ter Rho rats. PLoS One 7:e33266
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
Vasireddy, Vidyullatha; Chavali, Venkata R M; Joseph, Victory T et al. (2011) Rescue of photoreceptor degeneration by curcumin in transgenic rats with P23H rhodopsin mutation. PLoS One 6:e21193
Hiramatsu, Nobuhiko; Joseph, Victory T; Lin, Jonathan H (2011) Monitoring and manipulating mammalian unfolded protein response. Methods Enzymol 491:183-98
Lin, Jonathan H; Lavail, Matthew M (2010) Misfolded proteins and retinal dystrophies. Adv Exp Med Biol 664:115-21
Mahajan, Vinit B; Vallone, John G; Lin, Jonathan H et al. (2010) T-cell infiltration in autosomal dominant neovascular inflammatory vitreoretinopathy. Mol Vis 16:1034-40

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