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ER stress-induced translational regulation in retinal degeneration

视网膜变性中内质网应激诱导的翻译调节

基本信息

批准号：
10457483
负责人：
Deepika Vasudevan
金额：
$ 23.88万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457483
关键词：
5&apos Untranslated Regions Acute Address Affect Age Age related macular degeneration Atherosclerosis Biochemical Blindness Cellular Stress Chronic Data Destinations Development Diabetes Mellitus Disease Drosophila genus Embryo Endoplasmic Reticulum Etiology Feedback Fibroblasts Functional disorder G-Protein-Coupled Receptors Genes Genetic Genetic Diseases Genetic Screening Genetic Transcription Genetic Translation Goals Heritability Homeostasis Impairment Integral Membrane Protein Lead Learning Light Mammalian Cell Mediating Mentors Modeling Molecular Molecular Chaperones Mus Mutation Nature Neurodegenerative Disorders Open Reading Frames Pathologic Pathway interactions Patients Peptide Initiation Factors Pharmacologic Substance Phase Phosphorylation Phosphotransferases Photoreceptors Phylogenetic Analysis Property Protein Biosynthesis Proteins RNA interference screen Regulation Reporter Research Retina Retinal Degeneration Retinitis Pigmentosa Rhodopsin Role Signal Transduction Stress System Techniques Testing Therapeutic Training Transcript Transfer RNA Translating Translational Regulation Translational Repression Translations Work Yeasts age related attenuation base biological adaptation to stress design endoplasmic reticulum stress experimental study genome-wide inhibitor insight misfolded protein molecular pathology mutant protein folding response ribosome profiling therapeutic development therapeutic target transcription factor translation factor

项目摘要

PROJECT SUMMARY Autosomal Dominant Retinitis Pigmentosa (adRP) is a heritable retinal degeneration disorder that results in progressive vision loss and subsequent blindness. Nearly a third of adRP patients possess a mutation in the light-sensing G-protein coupled receptor, Rhodopsin. Many of these mutations cause the rhodopsin to misfold in the Endoplasmic Reticulum (ER) resulting ER dysfunction that leads to retinal degeneration. The age-related nature of the disease is likely because ER stress response pathways that protect against misfolded rhodopsins decline with age. A better understanding of these pathways may therefore contribute to therapeutic strategy development against adRP and other ER stress-mediated maladies. Here, I focus on one particular ER stress response pathway that is initiated by a transmembrane kinase, PERK. Upon sensing misfolded proteins, PERK phospho-inactivates a translation initiation factor, eIF2α, which inhibits protein synthesis and reduces ER burden. Interestingly, these inhibitory conditions stimulate the translation of a transcription factor, ATF4, due to its unusual 5'UTR. Our understanding of ATF4 induction is largely based on studies in yeast and remains incomplete, thus it remains possible that there are as yet unidentified translation regulators that specifically affect ATF4 translation but not canonical mRNA translation. In addition to translation regulation by phospho- eIF2α, the PERK pathway engages a second translational inhibition mechanism via 4E-BP, which is a direct transcriptional target of ATF4. With two translational inhibition mechanisms being activated by PERK signaling, how are stress responsive transcripts (that are required to ameliorate ER stress) translated? This proposal aims to address this major unanswered question regarding the PERK/ATF4 pathway by employing a Drosophila model of adRP to determine the pathological consequence of ATF4 signaling wherein mutant Rhodopsin-1 (Rh1G69D) imposes ER stress and leads to retinal degeneration. Preliminary studies were conducted by screening RNAi lines targeting various translation initiation factors for loss of an ATF4 reporter activity. This lead to the identification of a poorly characterized translational initiation factor as an unexpected regulator of ATF4. Experiments in cultured mouse embryonic fibroblasts (MEFs) shows a phylogenetically conserved role for this new factor in regulating ATF4 translation. Additional preliminary evidence indicates that the newly identified factor regulates translation at the 5' UTR ATF4. Part of the experiments outlined in this proposal is designed to determine how this factor regulates translation of ATF4 utilizing cutting-edge ribosome profiling techniques. The remainder of the proposal details a strategy to understand the role of the second translational inhibitor downstream of PERK, 4E-BP, in retinal degeneration. If realized, this project will significantly further our understanding of translation control during retinal degeneration in addition to providing valuable pharmaceutical targets for ER stress-mediated maladies.

项目总结