Delaying Cone Death in Retinitis Pigmentosa

描述（申请人提供）：人类和小鼠的视杆细胞和视锥细胞之间的神经元间关系是这样的，然而视杆细胞死亡总是导致视锥细胞死亡；视锥细胞的丢失对视杆细胞没有影响。这种现象在遗传性视网膜退行性疾病色素性视网膜炎中起重要作用，因为大多数已鉴定的致病等位基因编码的基因只在视杆细胞中表达。由于视锥细胞的死亡总是伴随着视杆细胞的死亡，而视锥细胞对于人类的视觉是至关重要的，正是它们的消失导致了失明。我们最近提出锥体死亡是由营养摄取减少引起的细胞自主事件，并表明胰岛素/AKT/mTOR通路在锥体死亡期间起着至关重要的作用。视网膜色素变性小鼠全身注射胰岛素可延长视锥细胞存活时间。在此，我们建议研究胰岛素如何延长锥体存活。为此，我们现在通过删除磷酸酶和紧张素同源物（PTEN）以及单独删除结节性硬化症复合体蛋白1 (TSC1)，从基因上激活了锥体中的通路。与胰岛素治疗相比，PTEN或TSC1的缺失进一步提高了视锥细胞存活率，这表明PTEN和TSC1下游基因具有延长色素性视网膜炎视力的治疗潜力。由于PTEN或TSC1的缺失激活了雷帕霉素（mTOR）和AKT激酶的机制靶点，因此预测促进锥体存活的基因位于这两种激酶的下游。由于mTOR和AKT有数百个靶点，我们将首先描述这两种激酶对细胞存活的贡献

DESCRIPTION (provided by applicant): 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.