权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting the retinoic acid signaling pathway for mitigating visual impairmen in retinal degenerative disorders

靶向视黄酸信号通路以减轻视网膜退行性疾病中的视力障碍

基本信息

批准号：
10298375
负责人：
RICHARD H KRAMER
金额：
$ 48.48万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298375
关键词：
Ablation Acute Age related macular degeneration Alcoholism Amacrine Cells Animal Model Behavior Behavioral Blindness Brain Cells Chemicals Clinical Research Conscious Contrast Sensitivity Darkness Degenerative Disorder Disease Disulfiram Dominant-Negative Mutation Electrophysiology (science)Enzymes Eye FDA approved Frequencies Functional disorder Gene Expression Generations Genes Genetic Transcription Goals Histologic Human Hyperactivity Impairment Individual Interneurons Light Light Cell Measures Morphology Mus Neurons Pharmaceutical Preparations Pharmacotherapy Phenotype Photophobia Photoreceptors Process Production Proteins Reporter Reporting Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinal Ganglion Cells Retinitis Pigmentosa Retinoic Acid Receptor Safety Signal Pathway Signal Transduction Synapses Testing Tetracyclines Therapeutic Time Toxic effect Training Transgenic Mice Tretinoin Viral Vision Visual Visual impairment avoidance behavior behavior test cellular targeting experimental study gene therapy improved in vivo inhibitor/antagonist mouse model multi-electrode arrays optogenetics patch clamp photoreceptor degeneration presynaptic neurons receptor response retinal neuron retinal rods safety testing small molecule spatial vision translation to humans visual information

项目摘要

ABSTRACT Light responses are initiated in rod and cone photoreceptors, processed by retinal interneurons, and synaptically transmitted to retinal ganglion cells (RGCs), which send information, in the form of spike trains, to the brain. In degenerative retinal disorders, including Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP), the photoreceptors gradually die off, depriving downstream neurons of light-sensitive input. However, recent evidence suggests that losing photoreceptors is only part of the problem in these disorders. Downstream retinal neurons become hyperactive, with retinal ganglion cells (RGCs) firing spontaneously in darkness at up to 10 times faster than in healthy retina, corrupting the proper encoding of visual information. We recently reported that retinoic acid (RA), a small molecule that activates gene transcription, is the signal that triggers RGC hyperactivity. Blocking the receptor for RA in vivo can reverse hyperactivity, unmasking light responses that would otherwise be obscured by spontaneous RGC firing. Blocking RA receptors in the retina also augments the contrast-sensitivity of learned visual behaviors in a mouse model of RP. Our goal in this project is to assess whether drugs or gene therapies that inhibit RA signaling can improve vision in mouse models of RP, with the hope of extending useful vision for years in humans with degenerative retinal disorders. First, we will ask whether inhibiting RA signaling not only improves light-sensitivity, but actually improves conscious visual function in vision-impaired mice, assessed with behavioral tests of contrast sensitivity and spatial frequency threshold. We will determine how when during the degeneration process RA inhibitors are most effective, revealing the optimal time for beginning treatment. Second, we will investigate retinal neurons that lie upstream of RGCs, namely bipolar cells and amacrine cells. We will ask whether pathophysiological changes in these presynaptic neurons are also induced by elevated RA signaling and whether inhibiting RAR can reverse these changes, providing critical information for effective cellular targeting of gene therapy. Third, we will test whether vision can be improved by inhibiting the enzyme that synthesizes RA, with a re-purposed drug that is already FDA-approved for other indications, paving the way for human clinical studies. Taken together, this project will establish the proof-of-principle behind a new treatment paradigm for augmenting vision in retinal degenerative disorders.

摘要