Delaying Cone Death in Retinitis Pigmentosa

延缓色素性视网膜炎中的视锥细胞死亡

基本信息

批准号：
8558356
负责人：
Claudio Punzo
金额：
$ 40.98万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8558356
关键词：
Ablation Affect Alleles Animals Blindness Candidate Disease Gene Cells Cessation of life Complete Blindness Complex Data Degenerative Disorder Dependence Disease Event Feedback Gene Activation Gene Expression Profiling Gene Targeting Gene Transfer Genes Genetic Goals Human Immunofluorescence Immunologic In Situ Hybridization Inherited Insulin Insulin Receptor Knockout Mice Mediating Metabolic Metabolism Mus Mutant Strains Mice Mutation Neurons Night Blindness Nutrient PTEN gene Pathway interactions Phosphatidylinositols Phosphotransferases Play Proto-Oncogene Proteins c-akt Recombinant adeno-associated virus (rAAV)Refractory Research Retina Retinal Cone Retinal Degeneration Retinitis Pigmentosa Rhodopsin Role Sampling Second Messenger Systems Sirolimus TSC2 gene Testing Therapeutic Tuberous sclerosis protein complex Vertebrate Photoreceptors Vision design disease-causing mutation efficacy testing human disease improved in vivo inherited retinal degeneration member mouse model overexpression phosphoric diester hydrolase public health relevance research study retinal rods second messenger treatment duration uptake

项目摘要

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.

描述（由申请人提供）：人类和小鼠的视杆细胞和视锥细胞光感受器之间的神经元间关系是这样的：视杆细胞的死亡总是导致视锥细胞的死亡；视锥细胞的损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视网膜色素变性中起着重要作用，因为大多数致病等位基因都编码专门在视杆细胞中表达的基因。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至关重要，因此正是视锥细胞的丧失导致了失明。我们最近提出视锥细胞死亡是由营养吸收减少引起的细胞自主事件，并表明胰岛素/AKT/mTOR通路在视锥细胞死亡期间发挥着至关重要的作用。对色素性视网膜炎小鼠全身注射胰岛素可延长视锥细胞存活时间。在这里，我们建议研究胰岛素如何延长视锥细胞的存活率。为此，我们现在通过删除磷酸酶和张力蛋白同源物 (PTEN) 以及分别删除结节性硬化症复合蛋白 1 (TSC1)，从基因上激活了视锥细胞中的通路。与注射胰岛素相比，PTEN 或 TSC1 的缺失进一步提高了视锥细胞的存活率，这表明 PTEN 和 TSC1 下游的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 的缺失会激活雷帕霉素 (mTOR) 和 AKT 激酶机制靶标，因此预计促进视锥细胞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视锥细胞存活的贡献 PTEN 或 TSC1 丢失。这些实验将在目标 1 和 2 中进行。随后，在目标 3 中，我们将使用微阵列来识别促进视锥细胞存活的 mTOR 和/或 AKT 靶基因。最后，我们将使用重组腺相关病毒介导的基因转移来测试这些基因在体内的功效。这些目标的实现将有助于设计合理的治疗方法来延长患有色素性视网膜炎的人类的视力。