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Characterization of RNA Binding Protein Regulation in Neural Stem Cell Quiescence Exit

神经干细胞静止退出中 RNA 结合蛋白调节的表征

基本信息

批准号：
10407981
负责人：
Bo Peng Lear
金额：
$ 3.08万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407981
关键词：
3&apos Untranslated Regions Address Adult Age Aging Amino Acids Antibodies Antisense RNA Anxiety Attenuated Automobile Driving Binding Binding Proteins Biological Assay Brain Cell Cycle Cell Line Cells Cognition Dementia Development Disease Elements Embryo Engineering G0 Phase Generations Genetic Transcription Genetic Translation Goals Hippocampus (Brain)Human Immunoprecipitation Impaired cognition In Vitro Injections Intermediate Filaments Knock-out Laboratories Mass Spectrum Analysis Measures Mediating Medical Mental Depression Messenger RNA Molecular Molecular and Cellular Biology Mood Disorders Mus Neurologic Neurons Open Reading Frames Pathology Physicians Physiological Play Post-Transcriptional Regulation Process Protein Biosynthesis Proteins RNA RNA-Binding Proteins Regulation Reporting Repression Research Role Scientist Shock Techniques Training Programs Transcript Translational Regulation Translational Repression Translations Universities Untranslated Regions Vimentin Western Blotting Wisconsin age related clinical practice cognitive function improved in vivo knock-down multicatalytic endopeptidase complex nerve stem cell neurogenesis newborn neuron novel overexpression programs protein aggregation psychologic responsible research conduct self-renewal skills stem stem cells therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT Neurogenesis, the lifelong generation of newborn neurons, occurs in neural stem cell (NSC) niches in the brain. A decline in neurogenesis occurs with aging but also contributes to disease pathologies such as dementia, anxiety and depression. This attenuated neurogenesis is largely the result of the increased barrier to NSC quiescence exit, the process of NSC activation and cell cycle reentry. NSCs dynamically transition between quiescent and activated cell states; quiescent NSCs (qNSCs) are in a reversible G0 state of the cell cycle whereas activated NSCs (aNSCs) divide to self-renew or produce new neurons. Despite quiescence exit being the rate-limiting step in neurogenesis, its mechanisms are not well understood. One key intrinsic mechanism influencing quiescence exit is aggregated protein clearance through the formation of aggresomes which are surrounded by the intermediate filament vimentin. In the absence of vimentin protein, there is decreased qNSC activation both in vivo and in vitro, suggesting that vimentin plays a crucial role in mediating quiescence exit. Interestingly, qNSCs uniquely contain high vimentin mRNA and low protein levels, compared to aNSCs, suggesting that the translational repression of vimentin mRNA in qNSCs is rapidly reversed during quiescence exit to upregulate vimentin protein, facilitating the formation of aggresomes. This indicates that the regulation of vimentin may be uniquely controlled in the transition between cell states. Thus, the identification of the mechanisms underlying this post-transcriptional regulation during quiescence exit will reveal processes that may be targeted to increase neurogenesis. The objective of this proposal is to identify key translational regulators, specifically RNA binding proteins (RBPs), controlling vimentin mRNA translation during NSC quiescence exit. We will characterize RBPs that bind vimentin mRNA preferentially in qNSCs, and establish their functional roles on vimentin mRNA translation, with the eventual goal of correlating post transcriptional mechanisms with the physiologic relevance of enhanced qNSC activation both in vitro and in vivo. Completion of this project will broaden the understanding of the molecular mechanisms underlying qNSC activation and present a potential novel mammalian therapeutic target to increase neurogenesis, with the goals of improving cognitive function with age. In addition to this research, the University of Wisconsin-Madison Medical Scientist Training Program and the Cellular and Molecular Biology graduate program will provide opportunities for advancing my skills in laboratory techniques, responsible conduct of research, professional development, and clinical practice necessary to become a successful independent Physician Scientist.

项目总结/摘要神经发生，新生神经元的终身生成，发生在神经干细胞（NSC）的小生境中，大脑神经发生的下降随着年龄的增长而发生，但也有助于疾病病理，如痴呆症，焦虑症和抑郁症这种减弱的神经发生在很大程度上是由于增加的屏障， NSC的休眠退出、NSC的激活和细胞周期的重新进入。神经干细胞在静止和活化细胞状态;静止NSC（qNSC）处于细胞周期的可逆G 0状态而活化的NSC（aNSC）分裂以自我更新或产生新的神经元。尽管静止出口作为神经发生的限速步骤，其机制尚不清楚。影响静止退出的一个关键内在机制是聚集的蛋白质通过形成被中间丝波形蛋白包围的侵袭体。在缺乏波形蛋白的情况下，在体内和体外qNSC的激活都减少，表明波形蛋白在体内起着至关重要的作用。在调解平静的出口。有趣的是，qNSC独特地含有高波形蛋白mRNA和低蛋白水平，与aNSC相比，表明qNSC中波形蛋白mRNA的翻译抑制被迅速逆转，在静止期退出时上调波形蛋白，促进侵袭体的形成。这表明波形蛋白的调节可能在细胞状态之间的转换中受到独特的控制。因此对这种转录后调控机制的识别将揭示出这些过程可能被靶向以增加神经发生。这个建议的目的是确定关键的翻译调节，特别是RNA结合蛋白质（RBP），控制波形蛋白mRNA的翻译在NSC静止退出。我们将描述 RBP在qNSCs中优先结合波形蛋白mRNA，并确定其对波形蛋白mRNA的功能作用翻译，最终目标是将转录后机制与生理相关性相关联，增强的qNSC激活在体外和体内。本项目的完成将拓宽对 qNSC激活的分子机制，并提出了一种潜在的新型哺乳动物治疗药物目标是增加神经发生，目的是随着年龄的增长改善认知功能。除此之外研究，威斯康星大学麦迪逊分校医学科学家培训计划和细胞和分子生物学研究生课程将提供机会，提高我的技能，在实验室技术，负责任的研究，专业发展和临床实践，成为一个成功的独立医生科学家。