Role of age-accumulated circRNAs in long-term memory

年龄累积的 circRNA 在长期记忆中的作用

• 批准号: 10019305
• 负责人: Pedro Miura
• 金额: $ 3.15万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019305
• 关键词: Administrative Supplement; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Behavior; Binding Proteins; Brain; CREB1 gene; Caenorhabditis elegans; Cognition; Cyclic AMP; Disease susceptibility; Elements; Global Change; Human; Impaired cognition; Individual; Instruction; Japan; Joints; Knowledge; Learning; Life; Longevity; Memory; Memory Loss; Methods; Molecular; Nematoda; Nervous System Physiology; Neurodegenerative Disorders; Neurons; Process; Research; Research Project Grants; Role; Synapses; Testing; Therapeutic Intervention; Tilia; Training; Work; age related; circular RNA; experience; genome-wide; long term memory; mutant; normal aging; parent grant; targeted treatment; tool; transcription factor

Project Summary for Supplemental Activities ONLY Age-related cognitive declines are prominent features of normal aging. Understanding the molecular changes and how nervous system function is altered by the process of aging is important to understand loss of memory with age and in neurodegenerative diseases. As in humans, the nematode C. elegans experiences cognitive declines during aging, but the causes of these declines are not well-understood. One good indicator of age- related changes in neuronal function are the levels of the transcription factor CREB (cAMP responsible element binding protein). Preliminary work from our parent grant has shown that removing the age-accumulated circular RNA, circ-crh-1, derived from the host CREB results in C. elegans with a longer mean life-span, suggesting that circ-crh-1 accelerates normal aging. CircRNAs may have roles in healthy brain function, particularly learning and memory, due to their localization at synapses; however, their direct role in long-term memory has never been tested. Moreover, altered circRNA levels have been found to be associated with neurodegenerative diseases such as Alzheimer’s. In this administrative supplement for the U.S.-Japan BRCP collaborative research initiative, we propose to (1) test generated mutants of circRNAs including circ-crh-1 in long-term associative memory (LTAM), and (2) use our developed tools to profile genome-wide expression changes of circRNAs before and after LTAM training. Through these studies, the contributions of specific circRNAs and their global changes in functional cognition will be used to identify the best targets of therapeutic intervention to treat cognitive decline with age. Our proposal is a joint effort from UNR (Drs. Miura and Van Der Linden) with OIST (Dr. Maruyama) in Japan, and provides unique opportunities for the PIs to learn sophisticated methods in LTAM. In return, the PIs will provide instruction to trainees in the host lab on aging and circRNA profiling analysis. The proposal aligns naturally with NIA’s plan and will significantly advance work on the parent grant (R21AG058955) to create new knowledge on the role of individual circRNAs in age-related behaviors such as cognitive decline.

仅补充活动的项目摘要 与年龄有关的认知下降是正常衰老的突出特征。了解分子变化 衰老过程如何改变神经系统功能对于了解记忆的丧失很重要 随着年龄和神经退行性疾病。就像在人类中一样，线虫秀丽隐杆线虫经历认知 衰老期间的下降，但是这些下降的原因并不理解。年龄的一个很好的指标 神经元功能的相关变化是转录因子CREB的水平（CAMP负责元素 结合蛋白）。我们父母赠款的初步工作表明，删除年龄耗尽的循环 RNA，cir-crh-1衍生自宿主CREB导致秀丽隐杆线虫具有较长的寿命，表明 CIRC-CRH-1加速正常衰老。 Circrnas可能在健康的大脑功能中扮演角色，尤其是学习和 记忆，由于它们在突触上的定位；但是，它们在长期记忆中的直接作用从未 测试。此外，已经发现改变的ciRCRNA水平与神经退行性疾病有关 例如阿尔茨海默氏症。在美国日本BRCP合作研究计划的行政补充中， 我们建议（1）在长期关联记忆中测试包括循环的CIRCRNA突变体 （LTAM）和（2）使用我们开发的工具来介绍circrnas的全基因组表达变化和 在LTAM培训之后。通过这些研究，特定的circrnas及其全球变化的贡献 功能认知将用于确定治疗性干预的最佳目标以治疗认知能力下降 随着年龄的增长。我们的建议是UNR（Miura博士和Van der Linden博士）与Oist（Maruyama博士）的共同努力。 日本，并为PI提供了独特的机会，可以在LTAM学习复杂的方法。作为回报，PI 将向主持人实验室的受训者提供有关衰老和Circrna分析分析的指导。该提案对齐 自然会使用NIA的计划，并会大大提高父母赠款（R21AG058955）的工作 关于单个CIRCRNA在年龄相关行为（例如认知能力下降）中的作用的知识。