Unfolded Protein Response in Eye Development and Disease

眼睛发育和疾病中未折叠的蛋白质反应

• 批准号: 10171856
• 负责人: HYUNG D RYOO
• 金额: $ 40.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171856
• 关键词: ATF6 gene; Affect; Alleles; Animal Model; Binding; Candidate Disease Gene; Cells; Data; Development; Disease; Drosophila eye; Drosophila genome; Drosophila genus; Endoplasmic Reticulum; Eukaryotic Cell; Eye; Eye Development; Eye diseases; Functional disorder; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Transcription; Goals; Homologous Gene; Human; Impairment; Inositol; Lead; Mammals; Mediating; Membrane Lipids; Missense Mutation; Modeling; Mus; Mutation; Nature; Normal Cell; Nuclear Hormone Receptors; Organism; Outcome; Palmitates; Pathway interactions; Peptides; Photoreceptors; Physiological; Proteins; RNA Interference; RXR; Reporting; Resistance; Retinal Degeneration; Retinitis Pigmentosa; Retinoids; Rhodopsin; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Source; Stress; Testing; Tretinoin; Yeasts; age related; base; biological adaptation to stress; cell type; cellular retinoic acid binding protein; chromophore; deprivation; endoplasmic reticulum stress; experimental study; fly; human disease; in vivo; insight; kohl; misfolded protein; mutant; novel therapeutic intervention; prevent; programs; response; sensor; therapeutic development; transcription factor

Project Summary The Unfolded Protein Response (UPR) refers to intracellular signaling pathways that are activated in response to endoplasmic reticulum (ER) stress. Efficient UPR signaling can help suppress diseases caused by misfolded proteins in the ER, such as those caused by mutant rhodopsins that underlie Retinitis Pigmentosa (RP). Conversely, defective UPR can lead to the dysfunction of certain cell types that are normally under physiological ER stress. The long term goal of this project is to understand the precise role and regulatory mechanisms of UPR in eye development and retinal degeneration. The current understanding of the UPR centers around ER stress sensor proteins that include IRE1 (Inositol Requiring 1), which detects misfolded peptides through a luminal peptide binding domain and initiates a branch of UPR signaling. In this proposal, we propose experiments that may change our basic understandings of UPR and its role in eye development and disease. Specifically in Aim 1, we plan to challenge the idea that IRE1-mediated UPR’s primary physiological role is to respond to misfolded peptides in the ER. IRE1 is required for normal Drosophila eye development, but contradicting the widely accepted role of IRE1 in detecting and responding to misfolded peptides, our preliminary studies indicate that IRE1’s developmental role is independent of its luminal domain that senses misfolded peptides. Based on this, I propose plans to test the idea that IRE1’s main role in the developing eye is not to help cells respond to unfolded proteins, but instead, to respond to other sources of physiological stress. In Aims 2 and 3, we will characterize a previously unrecognized UPR signaling branch. Specifically, we will test the hypothesis that retinoids, which are conjugated to properly folded rhodopsins to serve as chromophores, act as signaling molecules when released from misfolded rhodopsins to mediate Rhodopsin-1-specific UPR signaling. The possibility that retinoids actively regulate gene expression in Drosophila has thus far been largely overlooked. Our hypothesis is based in part on our unexpected preliminary data that retinoids can induce gene expression in Drosophila, and two such inducible genes highroad and fabp are involved in degrading mutant Drosophila Rhodopsin-1 alleles that are similar in their nature with human rhodopsin mutants that underlie RP. As part of this effort, we propose in Aim 2 to characterize the role of FABP, a Drosophila homolog of Cellular Retinoic Acid Binding Proteins, in retinoid-mediated gene expression control and retinal degeneration in the RP model. In Aim 3, we propose to identify the transcription factor that mediates retinoid signaling in Drosophila photoreceptors, and determine its role in mutant rhodopsin degradation and retinal degeneration. A successful outcome of these plans will significantly change our current understanding of UPR’s physiological role, and may contribute to the development of therapeutic strategies against diseases of the eye.

项目摘要 未折叠蛋白质反应（UPR）是指细胞内信号转导途径， 内质网应激。有效的UPR信号传导可以帮助抑制由错误折叠引起的疾病 ER中的蛋白质，例如由视网膜色素变性（RP）的基础的突变视紫红质引起的那些。 相反，缺陷的UPR可导致某些细胞类型的功能障碍，这些细胞类型通常处于生理学状态。 急诊室压力。本项目的长期目标是了解普遍定期审议的确切作用和监管机制 在眼睛发育和视网膜退化中的作用。目前对UPR的理解围绕着ER应力 传感器蛋白，包括IRE 1（肌醇需要1），它通过管腔蛋白检测错误折叠的肽， 肽结合结构域并启动UPR信号传导的分支。在这个提议中，我们提出的实验， 可能会改变我们对UPR及其在眼睛发育和疾病中的作用的基本理解。具体而言，在目标1中， 我们计划挑战IRE 1介导的UPR的主要生理作用是对错误折叠的细胞应答的观点。 ER中的肽。IRE 1是正常果蝇眼睛发育所必需的，但与广泛的 IRE 1在检测和响应错误折叠肽中的公认作用，我们的初步研究表明， IRE 1的发育作用不依赖于其感知错误折叠肽的管腔结构域。基于此，我 IRE 1在发育中的眼睛中的主要作用不是帮助细胞对未折叠的 蛋白质，而是对其他生理应激源做出反应。在目标2和3中，我们将描述 以前未识别的UPR信令分支。具体来说，我们将测试的假设，维甲酸，这是 与正确折叠的视紫红质结合，作为发色团，在释放时作为信号分子 从错误折叠的视紫红质介导视紫红质-1特异性UPR信号传导。类维生素A活性的可能性 调节果蝇基因表达的研究至今在很大程度上被忽视了。我们的假设部分基于 我们意想不到的初步数据表明，类维生素A可以诱导果蝇的基因表达， 基因highroad和fabp参与降解突变果蝇视紫红质-1等位基因， 他们的性质与人类视紫红质突变体的基础RP。作为这项工作的一部分，我们在目标2中建议， 描述FABP的作用，FABP是一种细胞视黄酸结合蛋白的果蝇同源物， RP模型中类维生素A介导的基因表达控制和视网膜变性。在目标3中，我们建议 鉴定在果蝇光感受器中介导类维生素A信号传导的转录因子，并确定其 在突变型视紫红质降解和视网膜变性中的作用。这些计划的成功结果将 显著改变我们目前对UPR生理作用的理解，并可能有助于 开发针对眼部疾病的治疗策略。