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Unfolded Protein Response in Drosophila models of Retinitis Pigmentosa

色素性视网膜炎果蝇模型中未折叠的蛋白质反应

基本信息

批准号：
10735578
负责人：
HYUNG D RYOO
金额：
$ 42.02万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735578
关键词：
ATF6 gene Acceleration Address Adult Affect Alleles Arrestins Binding CCAAT-Enhancer-Binding Proteins Cells Complex Coupled Data Dimerization Drosophila genus Drosophila melanogaster Endocytosis Endoplasmic Reticulum Endosomes Eye Family Feedback GTP-Binding Proteins Gene Expression Gene Expression Profiling Genes Genetic Genetic Diseases Genetic Models Goals Heterodimerization Heterozygote Homeostasis Homologous Gene Human Impairment Laboratories Light Link Mammals Mediating Membrane Modeling Mutation Organelles Outcome Pathologic Pathway interactions Patients Photoreceptors Physiological Play Property Proteins Quality Control Retina Retinal Degeneration Retinitis Pigmentosa Rhodopsin Role Signal Induction Signal Pathway Signal Transduction Site Stress Testing age related autosome bZIP Protein cell type chromophore endoplasmic reticulum stress experimental study fly genomic tools interest misfolded protein model organism mutant protein folding proteostasis response sensor trafficking transcription factor

项目摘要

Project Summary Rhodopsins are G-protein coupled proteins that initiate signal transduction in response to light exposure. There is significant interest in understanding Rhodopsin homeostasis because dysfunctional Rhodopsins are among the most frequent causes of Retinitis Pigmentosa (RP), a genetic disorder with age-related retinal degeneration. Among those associated with RP are Rhodopsin mutants with impaired protein folding properties. Because Rhodopsins undergo synthesis and folding in the endoplasmic reticulum (ER), such Rhodopsin mutants could impose stress on this organelle. Those conditions activate an adaptive signaling response that regulates gene expression, widely referred to as the Unfolded Protein Response (UPR). One particular UPR signaling branch relevant to this proposal is the one mediated by the ER stress sensor PERK and its downstream effector ATF4. Among others, UPR signaling induces the expression of genes that help fold or degrade misfolded proteins in the ER, thereby affecting retinal degeneration in RP. The basic mechanisms of UPR signaling, Rh1 homeostasis, and retinal degeneration are conserved in Drosophila melanogaster. Specifically, Drosophila ninaE encodes the Rhodopsin-1 (Rh1) protein expressed in adult eye photoreceptors. A mutant allele of this gene, ninaEG69D, serves as a model for RP as it imposes ER stress, activates the UPR, and dominantly causes age-related retinal degeneration. The long-term goal of this project is to harness the genetic and genomic tools of Drosophila to understand the role of UPR in retinal degeneration. Here, I propose to investigate new UPR signaling branches that may significantly change our understanding of Rhodopsin homeostasis and retinal degeneration. In Specific Aims 1 and 2, I propose to re-evaluate the widespread idea that ATF4 is the primary downstream effector of PERK-mediated UPR. Arguing against this, we recently identified a new sub-branch of the PERK pathway mediated by Xrp1, a bZIP transcription factor. How Xrp1 is regulated and whether it affects retinal degeneration remains unclear. We will specifically test the hypothesis that Xrp1 is translationally induced by PERK. We will determine if such induction affects the course of retinal degeneration and whether Xrp1 requires heterodimerization partners to regulate some or all downstream target genes. I further propose to identify the human equivalent of the Xrp1 heterodimer complex. In Aim 3, I propose to investigate a possible link between ER stress and endosome trafficking in the RP model. Most UPR studies have focused on its role in ER homeostasis. However, our recent gene expression profiling results reveal that ninaEG69D/+ photoreceptors also induce many endosomal trafficking regulators. I propose to determine if those endosomal factors are induced by the UPR or by other unconventional signaling pathways. We will further determine if those pathways affect Rhodopsin homeostasis and the course of retinal degeneration in this RP model. A successful outcome of these plans may help significantly change our current understanding of UPR signaling pathways and retinal degeneration in RP.

项目摘要视紫红质是G蛋白偶联蛋白，其响应于光暴露而启动信号转导。那里是理解视紫红质稳态的重要兴趣，因为功能失调的视紫红质是其中之一，视网膜色素变性（RP）是一种遗传性疾病，与年龄相关的视网膜变性的最常见原因。与RP相关的是具有受损蛋白质折叠特性的视紫红质突变体。因为视紫红质在内质网（ER）中进行合成和折叠，这样的视紫红质突变体可以对这个细胞器施加压力。这些条件激活了一种适应性信号反应，这种蛋白质表达被广泛称为未折叠蛋白质反应（UPR）。一个特定的UPR信令分支与该提议相关的是由ER应激传感器PERK及其下游效应物ATF 4介导的。其中，UPR信号诱导基因的表达，这些基因帮助折叠或降解细胞中错误折叠的蛋白质。 ER，从而影响RP中的视网膜变性。UPR信号转导、Rh 1稳态、和视网膜变性在果蝇中是保守的。具体来说，果蝇ninaE编码视紫红质-1（Rh 1）蛋白在成人眼光感受器中表达。该基因的突变等位基因ninaEG 69 D，作为RP的模型，因为它施加ER应激，激活UPR，并主要引起年龄相关的视网膜病变。退化该项目的长期目标是利用果蝇的遗传和基因组工具，了解UPR在视网膜变性中的作用。在这里，我建议研究新的UPR信号分支这可能会极大地改变我们对视紫红质稳态和视网膜变性的理解。在特定目的1和2，我建议重新评估广泛的想法，即ATF 4是主要的下游效应子。 PERK介导的UPR。与此相反，我们最近发现了PERK通路的一个新分支由Xrp 1介导，一种bZIP转录因子。Xrp 1如何调节以及它是否影响视网膜变性仍不清楚我们将专门测试Xrp 1是由PERK诱导的假设。我们将确定这种诱导是否影响视网膜变性的过程，以及Xrp 1是否需要异二聚化配偶体调节一些或所有下游靶基因。我进一步建议确定 Xrp 1异二聚体复合物的人类等价物。在目标3中，我建议研究ER与 RP模型中的应力和内体运输。大多数UPR研究都集中在其在ER稳态中的作用。然而，我们最近的基因表达谱分析结果表明，ninaEG 69 D/+光受体也诱导许多细胞凋亡，内体运输调节因子。我建议确定这些内体因子是否由UPR诱导，通过其他非传统的信号途径。我们将进一步确定这些通路是否影响视紫红质在该RP模型中，视网膜变性的动态平衡和过程。这些计划的成功结果可能有助于显著改变我们目前对RP中UPR信号通路和视网膜变性的理解。