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Ribosome-Associated Regulation of Yeast Prion Formation

酵母朊病毒形成的核糖体相关调控

基本信息

批准号：
9812475
负责人：
Dale Cameron
金额：
$ 41.94万
依托单位：
URSINUS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9812475
关键词：
Alzheimer&apos s Disease Amyloid Biochemical Biogenesis Biological Biology Cell Nucleus Cell physiology Cells Complex Data Data Analyses Data Collection Development Disease Event Experimental Designs Exposure to Foundations Gene Expression Genetic Glucose Goals High Prevalence Human Individual Intervention Knowledge Lead Literature Measurement Mediating Metabolism Mission Modeling Molecular Conformation National Institute of General Medical Sciences Neurodegenerative Disorders Outcome Parkinson Disease Pathologic Pharmacology Phenotype Physiological Play Population Positioning Attribute Prevention strategy Prion Diseases Prions Process Proteins Proteome Public Health Publications Publishing Quality Control RNA Processing Regulation Reporter Research Resistance Review Literature Ribosomes Role Saccharomyces cerevisiae Schools Science Stimulus Stress Stress-Induced Protein Students System Testing Therapeutic Intervention Time Transcription Coactivator Translating United States National Institutes of Health Variant Work Yeast Model System Yeasts amyloid formation amyloidogenesis base biological adaptation to stress career college experimental study innovation mortality polypeptide prion hypothesis protein aggregate protein aggregation protein misfolding protein phosphatase inhibitor-2 response symposium targeted treatment undergraduate student yeast prion

项目摘要

Project Summary/Abstract Whether amyloid formation in stress conditions serves any beneficial purpose or is instead simply a pathologic outcome of the stress is an important open question. Elucidating the cellular triggers and physiological consequences of amyloid formation therefore represents a critical barrier to advancing our understanding of amyloid biology. The applicant’s long-term goal is to use the highly facile yeast model system to understand the stimuli that trigger amyloid formation, the mechanisms underlying this response, and its physiological significance. The central objective of this proposal is to decipher the ribosome-associated mechanisms that regulate prion formation for a variety of natural and artificial yeast prions and the impact of prion formation on gene expression and metabolism. The central hypothesis is that ribosome-associated factors, such as the ribosome-associated complex (RAC) and the nascent polypeptide-associated complex (NAC), play a central role in regulating prion formation in response to environmental stimuli and that the resulting prion phenotypes have important physiological implications. The hypothesis is based on the applicant’s published work and preliminary data. The rationale for the proposed research is that elucidating the contributions of ribosome-associated processes in prion formation is a critical step in understanding the regulation and physiological impacts of amyloid formation to facilitate pharmacological manipulation. Using the naturally occurring yeast prions [PSI+], [URE3] and [RNQ+] as models, along with artificially constructed yeast prions, this hypothesis will be tested by pursuing two related but independent specific aims: 1) Identify the roles of RAC and NAC in stress-induced protein aggregation and prion formation; and 2) Determine the impact of prion induction on gene expression and metabolism. The proposed work is innovative because it represents a substantial departure from the status quo by examining the earliest possible time-point in prionogenesis – during synthesis of the prion-forming protein – and by assessing the physiological consequences of prion switching. Additionally, these experiments will be enriched by the applicant’s development of an innovative new prion reporter system that enables rapid, quantitative measurements of prion formation and prion variant strength in individual cells in real time. The contribution of the proposed research is expected to be the elucidation of ribosome-associated mechanisms regulating amyloid formation and the resulting consequences on cellular physiology. This contribution will be significant because co-translational amyloid formation constitutes the earliest misfolding event against which pharmacological intervention could be targeted; thus, an understanding of the underlying triggers and regulatory mechanisms of co-translational amyloidogenesis is urgently needed to advance the field and could provide a basis for targeting mammalian homologs in pharmacological interventions of mammalian protein misfolding disorders.

项目总结/文摘