The inter-neuronal relationship between rod and cone photoreceptors in human and mouse is such that rod death always leads to cone death however;loss of cones has no effect on rods. This phenomenon plays an important role in the inherited retinal degenerative disease retinitis pigmentosa, as most disease-causing alleles identified encode for genes that are exclusively expressed in rods. Since cone death always follows rod death, and cones are essential for human vision, it is their loss that leads to blindness. We have recently proposed that cone death is a cell autonomous event caused by reduced nutrient uptake and showed that the insulin/AKT/mTOR pathway plays a crucial role during the periods of cone death. Systemic administration of insulin to retinitis pigmentosa mice prolongs cone survival. Here we propose to study how insulin prolongs cone survival. To that end we have now genetically activated the pathway in cones, by deletion of the phosphatase and tensin homolog (PTEN) and separately, by deletion of the tuberous sclerosis complex protein 1 (TSC1). Loss of PTEN or TSC1 further improves cone survival when compared to insulin administration, suggesting that genes downstream of PTEN and TSC1 have therapeutic potential to prolong vision in retinitis pigmentosa. Since loss of PTEN or TSC1 activates the kinases mechanistic target of rapamycin (mTOR) and AKT, genes that promote cone survival are predicted to be downstream of these two kinases. Because mTOR and AKT have hundreds of targets we will first delineate the contribution of these two kinases to cone survival seen upon loss of PTEN or TSC1. These experiments will be carried out in aims 1 &2. Subsequently, in aim 3 we will use microarrays to identify target genes of mTOR and/or AKT that promote cone survival. Finally, we will tests the efficacy of such genes in vivo using recombinant Adeno-associated virus mediated gene transfer. Accomplishment of these aims will help design rational therapeutic approaches to extend vision in humans with retinitis pigmentosa.

Public Health Relevance

Retinitis pigmentosa is an inherited retinal degenerative disease that is largely untreatable. Most disease causing mutations encode for genes that are exclusively expressed in the night active rods. Consequently, night blindness is the first pathological sign of the disease. However, even though the mutation does not affect a gene that is expressed in the day active cones, loss of rods results eventually in tunnel vision and then complete blindness. Why cones die when rods die remains unknown. We have recently shown that during cone death cones are nutritionally deprived and that treatment of mice with insulin prolongs cone survival. In this project we aim at studying how insulin can prolong cone survival in order to develop rational therapeutic strategies for this blinding disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Shen, Grace L
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University of Massachusetts Medical School Worcester
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Petit, Lolita; Ma, Shan; Cipi, Joris et al. (2018) Aerobic Glycolysis Is Essential for Normal Rod Function and Controls Secondary Cone Death in Retinitis Pigmentosa. Cell Rep 23:2629-2642
Venkatesh, Aditya; Cheng, Shun-Yun; Punzo, Claudio (2017) Loss of the cone-enriched caspase-7 does not affect secondary cone death in retinitis pigmentosa. Mol Vis 23:944-951
Petit, Lolita; Ma, Shan; Cheng, Shun-Yun et al. (2017) Rod Outer Segment Development Influences AAV-Mediated Photoreceptor Transduction After Subretinal Injection. Hum Gene Ther 28:464-481
Petit, Lolita; Khanna, Hemant; Punzo, Claudio (2016) Advances in Gene Therapy for Diseases of the Eye. Hum Gene Ther 27:563-79
Camacho, Erika T; Punzo, Claudio; Wirkus, Stephen A (2016) Quantifying the metabolic contribution to photoreceptor death in retinitis pigmentosa via a mathematical model. J Theor Biol 408:75-87
Venkatesh, A; Ma, S; Punzo, C (2016) TSC but not PTEN loss in starving cones of retinitis pigmentosa mice leads to an autophagy defect and mTORC1 dissociation from the lysosome. Cell Death Dis 7:e2279
Zieger, Marina; Punzo, Claudio (2016) Improved cell metabolism prolongs photoreceptor survival upon retinal-pigmented epithelium loss in the sodium iodate induced model of geographic atrophy. Oncotarget 7:9620-33
Petit, Lolita; Punzo, Claudio (2016) Gene therapy approaches for the treatment of retinal disorders. Discov Med 22:221-229
Venkatesh, Aditya; Ma, Shan; Le, Yun Z et al. (2015) Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice. J Clin Invest 125:1446-58
Ma, Shan; Venkatesh, Aditya; Langellotto, Fernanda et al. (2015) Loss of mTOR signaling affects cone function, cone structure and expression of cone specific proteins without affecting cone survival. Exp Eye Res 135:1-13

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