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Stress Granules in Yeast and Mammals

酵母和哺乳动物中的应激颗粒

基本信息

批准号：
9514344
负责人：
ROY PARKER
金额：
$ 31.51万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9514344
关键词：
ATP phosphohydrolase Address Affect Alternative Splicing Amyotrophic Lateral Sclerosis Base Pairing Binding Proteins Cytoplasmic Granules Disease Disease Progression Event Frontotemporal Lobar Degenerations Gene Expression Genetic Translation Goals Grant Inclusion Bodies Length Maintenance Mammals Maps Membrane Messenger RNA Methodology Modeling Muscle Mutation Myopathy Neurodegenerative Disorders Neurons Osteitis Deformans Pathologic Pathology Play Production Proteins Proteome RNA RNA Helicase RNA-Binding Proteins Reporter Role Specificity Stress Synaptic plasticity Testing Tissues Translation Initiation Translations Work Yeasts amyloid formation base biological adaptation to stress crosslink experimental study insight mRNA Decay mRNA Stability messenger ribonucleoprotein mitochondrial membrane novel protein TDP-43 protein aggregate recruit self assembly transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY The goals of this grant are to understand the assembly, dynamics, and functions of stress granules in the control of gene expression. Stress granules are cytoplasmic granules of untranslating mRNAs and proteins that form when translation initiation is limiting. Stress granules are important for three reasons. First, they sequester mRNAs and mRNA binding proteins and are thought to play a role in regulating the translation or degradation of its resident mRNAs, particularly during stress. Second, assemblies related to stress granules form in neurons and play a role in modulating synaptic plasticity (McCann et al., 2011; Barbee et al., 2006). Thus, understanding stress granules will help to understand other similar mRNP assemblies. Finally, aberrant stress granule accumulation appears to be a causative event in a multisystem pathology, referred to as inclusion body myopathy (IBM) that includes Amyotrophic Lateral Sclerosis (ALS), Frontotemporal lobar degeneration (FTLD), Paget's disease of bone and some muscle myopathies. These diseases can be caused by mutations in RNA binding proteins, such as hnRNPA1 or TDP-43, which increase stress granule assembly and amyloid formation, or by mutations in the AAA-ATPase VCP, which decrease stress granule clearance. Moreover, these diseases are characterized by the presence of cytoplasmic RNA-protein aggregates that contain markers of stress granules. Given this importance in both normal stress responses and in pathological conditions, an understanding of normal and aberrant stress granule formation and function is critical. In this grant, we build on our recent analyses of the stress granule proteome and transcriptome to determine the effect of stress granule formation on mRNA function, the mechanisms that target mRNAs to stress granules, and the novel role of mRNA-mRNA interactions in trans on the assembly and maintenance of stress granules. The specific questions addressed in this proposal are: I) What is the impact of stress granule assembly on mRNA stability and decay? II) What are the mechanisms of mRNA partitioning into stress granules? III) What is the role of RNA-RNA interactions in stress granule assembly? Completion of these aims will reveal fundamental principles of stress granule assembly and function, including insights into how pathological RNP granules form and impact gene expression in affected tissues.

项目总结