Dysregulation of VEGF RNA Stability in Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症中 VEGF RNA 稳定性失调

• 批准号: 7692190
• 负责人: Liang Lu
• 金额: $ 14.58万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7692190
• 关键词: 3' Untranslated Regions; Affect; Amyotrophic Lateral Sclerosis; Antioxidants; Astrocytes; Cell model; Cells; Cellular Stress; Cessation of life; Coculture Techniques; Code; Complex; Cuprozinc Superoxide Dismutase; Disease; Down-Regulation; Elements; Enzymes; Familial Amyotrophic Lateral Sclerosis; Functional disorder; Genes; Genetic Transcription; Growth Factor; HuR protein; Hypoxia; In Vitro; Indium; Inflammatory; Inherited; Instruction; Investigation; Link; Messenger RNA; Modeling; Molecular; Motor Neurons; Mus; Mutant Strains Mice; Mutation; Neuroglia; Neurons; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Proteins; RNA; RNA Processing; RNA Stability; Role; Signal Transduction; Stress; Superoxide Dismutase; Testing; Therapeutic Intervention; Tissues; Transcript; Up-Regulation; Vascular Endothelial Growth Factors; cytokine; genetic linkage; insight; motor neuron degeneration; mutant; mutant mouse model; neuroprotection; protein expression; relating to nervous system; response

DESCRIPTION (provided by applicant): Project Summary: Amyotrophic lateral sclerosis (ALS) is a devastating disease. Recent evidence indicates that vascular endothelial growth factor (VEGF) is a critical element for neuroprotection during cellular stress, and that its down-regulation in neural tissues contributes to accelerated motor neuron death. One molecular pathway that promotes VEGF up-regulation in response to cellular stress is RNA stabilization. When cells are exposed to stress, such as hypoxic exposure, oxidative metabolites, or inflammatory cytokine exposure, however, the VEGF transcript becomes stabilized, resulting in enhanced expression and subsequent neuroprotection. In our preliminary studies with the superoxide dismutase (SOD1) mutant mouse model of ALS, we have observed a marked diminution of VEGF mRNA levels that is linked to VEGF RNA destabilization. In this proposal, we will test two closely related hypotheses: 1) VEGF destabilization and down-regulation is due to dysfunction of the RNA stabilizer, HuR, in the presence of mutant SOD1. 2) Intercellular signaling between astrocytes and neurons triggers the aberrant VEGF mRNA stabilization response. Three specific aims are proposed to test these hypotheses. First, we will investigate the role of cytoplasmic HuR translocation and mutant SOD1 in the destabilization and down-regulation of VEGF mRNA. Second, we will analyze the interaction between mutant SOD1 proteins, HuR and the RNP complex associated with the VEGF 3'UTR to determine why mutant SOD1 negatively affects VEGF RNA processing. Third, we will investigate the impact of the mutant SOD1-induced VEGF destabilization in a co-culture model of motor neuron-like cells and glial cells that express wild-type or mutant SOD1. Relevance: This proposal has the promise to elucidate the mechanism by which VEGF is down regulated in mutant SOD1 mice, and to provide a possible molecular link between two important aspects of ALS pathology: VEGF and SOD1 mutant proteins. Further investigation of this link could provide insight into the pathogenesis of ALS, and ultimately therapeutic intervention for this currently incurable disorder.

项目简介：肌萎缩性侧索硬化症（ALS）是一种毁灭性的疾病。最近的证据表明，血管内皮生长因子（VEGF）是细胞应激时神经保护的关键因素，其在神经组织中的下调有助于加速运动神经元的死亡。在细胞应激反应中促进VEGF上调的一个分子途径是RNA稳定。然而，当细胞暴露于应激时，如缺氧暴露、氧化代谢物暴露或炎症细胞因子暴露，VEGF转录物变得稳定，导致表达增强和随后的神经保护。在我们对ALS的超氧化物歧化酶（SOD1）突变小鼠模型的初步研究中，我们观察到VEGF mRNA水平的显著降低，这与VEGF RNA的不稳定有关。在本提案中，我们将检验两个密切相关的假设：1)在突变体SOD1存在下，VEGF的不稳定和下调是由于RNA稳定剂HuR的功能障碍。2)星形胶质细胞和神经元之间的细胞间信号传导触发异常的VEGF mRNA稳定反应。本文提出了三个具体目标来检验这些假设。首先，我们将研究细胞质HuR易位和突变SOD1在VEGF mRNA失稳和下调中的作用。其次，我们将分析突变SOD1蛋白、HuR和与VEGF 3'UTR相关的RNP复合物之间的相互作用，以确定为什么突变SOD1会对VEGF RNA加工产生负面影响。第三，我们将在表达野生型或突变型SOD1的运动神经元样细胞和胶质细胞共培养模型中研究突变型SOD1诱导的VEGF不稳定的影响。相关性：本研究有望阐明SOD1突变小鼠中VEGF下调的机制，并在ALS病理的两个重要方面：VEGF和SOD1突变蛋白之间提供可能的分子联系。对这一联系的进一步研究可能有助于深入了解ALS的发病机制，并最终对这种目前无法治愈的疾病进行治疗干预。