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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

基本信息

批准号：
8774160
负责人：
PETER H KING
金额：
--
依托单位：
BIRMINGHAM VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8774160
关键词：
3&apos Untranslated Regions Address Affect Affinity Amyotrophic Lateral Sclerosis Animals Apoptosis Area Astrocytes BCL2 gene BIRC4 gene Binding Cancer Model Cell Survival Cell model Cells Cellular Stress Cessation of life Code Complex Cuprozinc Superoxide Dismutase Degenerative Disorder Disease Elements Event Familial Amyotrophic Lateral Sclerosis Foundations Functional disorder Gene Expression Genes Genetic Translation Genetic study 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 antioxidant enzyme 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

项目摘要

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.

描述（由申请人提供）：