RNA-Targeted Dysregulation of Survival Factors in ALS: HuR to the Rescue

ALS 中生存因子的 RNA 靶向失调：HuR 来拯救

• 批准号: 8242240
• 负责人: PETER H KING
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242240
• 关键词: 3' Untranslated Regions; Address; Affect; Affinity; Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Apoptosis; Area; Astrocytes; BIRC4 gene; Binding; Cancer Model; Cell Survival; Cell model; Cells; Cellular Stress; Cessation of life; Code; Complex; Cuprozinc Superoxide Dismutase; Degenerative Disorder; Disease; Elements; Enzymes; Event; Familial Amyotrophic Lateral Sclerosis; Foundations; Functional disorder; Gene Expression; Genes; Genetic Translation; Growth; Growth Factor; Healthcare; Human Genetics; In Vitro; Incidence; Laboratories; Lead; Light; Link; Location; MDM2 gene; Maintenance; Messenger RNA; Mission; Molecular; Motor Neuron Disease; Motor Neurons; Muscle; Mutation; Neurodegenerative Disorders; Paralysed; Pathogenesis; Pathway interactions; Phenotype; Play; Polyribosomes; Population; Post-Transcriptional RNA Processing; Process; Production; Progressive Disease; Proteins; RNA; RNA Binding; RNA Degradation; RNA Stability; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Regulatory Element; Research; Role; Testing; Transcript; Transgenic Organisms; Translations; Up-Regulation; Vascular Endothelial Growth Factors; Veterans; War; Work; base; cytotoxic; effective therapy; gain of function; in vitro Model; in vivo; mRNA Stability; mitochondrial dysfunction; motor neuron degeneration; mouse model; mutant; novel; novel therapeutic intervention; protein TDP-43; superoxide dismutase 1

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons that inexorably leads to progressive weakness and death. The incidence of ALS is significantly increased among veterans of foreign wars, and thus it has a major impact on veteran health care. Sadly, the pathophysiology of this disease remains largely a mystery, and there are no effective treatments. In recent work from our laboratory, we have identified dysregulation of growth factor mRNA stability and translation as a novel mechanistic direction to understanding the basis for ALS. Mutations of Cu, Zn superoxide dismutase (SOD)1 that are associated with familial ALS gain a high RNA binding affinity for U- and AU-rich elements present in 5' and 3' untranslated regions (UTR) of many critical growth and cytoprotective factors. Through an interaction with cellular RNA binding proteins (RBP), these elements govern stability and translation of the transcript and provide an important pathway for rapid upregulation of survival factors during cellular stress. The RBP, HuR, plays a major positive role in this molecular pathway by binding to these elements. We previously showed that mutant SOD1, through its gain of high RNA binding affinity, disrupts HuR stabilization and translation of vascular endothelial growth factor mRNA, a critical neuroprotective factor for motor neurons. We found that apoptosis and mitochondrial dysfunction in cells expressing mutant SOD1 could be reversed by upregulating HuR. Based on this work, we hypothesize here that upregulation of HuR can rescue motor neuron degeneration induced by mutant SOD1 by reversing aberrant post-transcriptional processing of survival factor mRNAs in motor neurons directly or by enhanced VEGF production of surrounding astrocytes. We have the animal cellular models necessary to test this exciting possibility. This work has the real potential to establish a foundation for developing novel therapeutic approaches to this devastating disease. Specific Aims: 1. To determine whether HuR can rescue the cytotoxic phenotype of mutant SOD1 in motor neurons and astrocytes using in vitro and in vivo mouse models. 2. To determine the molecular impact of transgenic HuR expression in motor neurons and astrocytes with regard to posttranscriptional regulation and production of cytoprotective factors. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis is a relentless disease of motor neurons that leads to progressive paralysis of the muscles and ultimately death. There is a significantly increased incidence of this disease in our veterans of foreign wars, and there is no cure or mitigating therapy. This proposal will address a novel area of growth factor regulation that may contribute to the cause of this disease, and thus may ultimately lead to novel therapies.

描述（由申请人提供）： 肌萎缩侧索硬化症（ALS）是一种运动神经元的退行性疾病，它无情地导致进行性虚弱和死亡。ALS的发病率在国外战争的退伍军人中显着增加，因此它对退伍军人的医疗保健产生了重大影响。可悲的是，这种疾病的病理生理学在很大程度上仍然是一个谜，没有有效的治疗方法。在我们实验室最近的工作中，我们已经确定了生长因子mRNA稳定性和翻译的失调作为理解ALS基础的新机制方向。与家族性ALS相关的Cu，Zn超氧化物歧化酶（SOD）1突变获得了对存在于许多关键生长和细胞保护因子的5'和3'非翻译区（UTR）中的富含U和AU的元件的高RNA结合亲和力。通过与细胞RNA结合蛋白（RBP）的相互作用，这些元件控制转录物的稳定性和翻译，并为细胞应激期间存活因子的快速上调提供重要途径。RBP，HuR，通过与这些元件结合在该分子途径中发挥主要的积极作用。我们以前表明，突变体SOD1，通过其获得高RNA结合亲和力，破坏HuR稳定和血管内皮生长因子mRNA的翻译，运动神经元的一个关键的神经保护因子。我们发现，细胞凋亡和线粒体功能障碍，表达突变SOD 1可以逆转上调HuR。基于这项工作，我们在这里假设，上调HuR可以拯救运动神经元变性诱导的突变体SOD 1逆转运动神经元中的生存因子mRNA的转录后处理异常直接或周围的星形胶质细胞的VEGF的生产增强。我们有必要的动物细胞模型来测试这种令人兴奋的可能性。这项工作有真实的潜力为开发这种毁灭性疾病的新治疗方法奠定基础。具体目标：1。使用体外和体内小鼠模型确定HuR是否可以挽救运动神经元和星形胶质细胞中突变SOD 1的细胞毒性表型。2.确定转基因HuR在运动神经元和星形胶质细胞中表达对转录后调节和细胞保护因子产生的分子影响。 公共卫生关系： 肌萎缩侧索硬化症是一种无情的运动神经元疾病，导致肌肉进行性瘫痪，最终死亡。在我们参加过对外战争的退伍军人中，这种疾病的发病率显著增加，而且没有治愈或缓解治疗方法。这项提案将解决一个新的领域的生长因子调节，可能有助于这种疾病的原因，从而可能最终导致新的疗法。