Role of age-accumulated circRNAs in long-term memory

仅补充活动的项目摘要 与衰老相关的认知能力下降是正常衰老的显著特征。了解分子变化 以及神经系统的功能是如何随着年龄的增长而改变的， 与年龄和神经退行性疾病有关。和人类一样，线虫C. elegans经验认知 在衰老过程中下降，但这些下降的原因还不清楚。一个很好的年龄指标- 神经元功能的相关变化是转录因子CREB（cAMP负责元件）的水平 结合蛋白）。我们的父母补助金的初步工作表明， 来源于宿主CREB的RNA（circ-crh-1）导致C.平均寿命更长的线虫，这表明， CIRC-CRH-1加速正常老化。CircRNA可能在健康的大脑功能中发挥作用，特别是学习和 记忆，由于其在突触的本地化;然而，他们在长期记忆中的直接作用从来没有 测试.此外，研究发现circRNA水平的改变与神经退行性疾病有关 比如老年痴呆症在美国的这份行政补充文件中-日本BRCP合作研究倡议， 我们提出（1）在长期联想记忆中测试产生的包括circ-crh-1的circRNA突变体 （LTAM），和（2）使用我们开发的工具来分析circRNA的全基因组表达变化， 经过LTAM培训后通过这些研究，特定的circRNA的贡献和它们的全球变化， 功能性认知将被用来确定治疗认知功能下降的最佳干预目标 随年龄我们的建议是UNR（三浦博士和货车德林登）与OIST（丸山博士）的共同努力， 日本，并提供独特的机会，PI学习复杂的方法，在LTAM。作为回报， 将在主实验室为学员提供关于衰老和circRNA分析的指导。该提案与 自然与NIA的计划，并将显着推进工作的父母补助金（R21 AG 058955），以创造新的 关于个体circRNA在年龄相关行为（如认知衰退）中的作用的知识。

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.