Molecular Mechanisms Regulating Age-Related Cognitive Decline in C. elegans

描述(申请人提供)：线虫和人类一样，随着年龄的增长，认知功能会下降，但这些下降的原因尚不清楚。我们建议识别神经功能中与年龄相关的变化，并区分那些功能有害的变化和那些可能是对衰老的适应性反应的变化。在我们的第一个目标中，我们将识别长期联想记忆(LTAM)所需的随年龄变化和功能降低的基因，并通过对候选基因的操纵来修复随年龄增长的功能。我们的第二个目标是识别参与LTAM的细胞，并描述它们在LTAM过程中的角色。此外，我们将评估细胞功能随年龄的变化。最后，我们将比较正常衰老过程中的变化与两种线虫痴呆模型中的病理变化。与痴呆症模型的比较将区分健康和病理性的年龄相关性变化。通过这些研究，将利用特定成分对功能认知的贡献来确定治疗干预的最佳靶点，以治疗随年龄增长的认知衰退。 公共卫生相关性：在我们的工作中，我们建议使用模式生物秀丽线虫来发现其功能变化与认知能力随年龄下降相关的基因。我们设计了一项对这种有机体进行长期记忆的测试，并观察到这些动物随着年龄的增长失去了记忆能力。利用这项测试和各种分子工具，我们可以研究导致记忆随年龄增长和神经退行性疾病的基因和细胞。

DESCRIPTION (provided by applicant): C. elegans, like humans, experience cognitive functional declines with age, but the cause of these declines are not yet known. We propose to identify age-related changes in neuronal function, and to distinguish those changes that are functionally deleterious from those that may be an adaptive response to aging. In our first Aim, we will identify the genes required for long-term associative memory (LTAM) that change with age and with decreased function, and rescue function with age through manipulation of candidate genes. Our second Aim focuses on the identification of the cells involved in LTAM, and the characterization of their roles in the LTAM process. Furthermore, we will assess changes in cellular function with age. Finally, we will compare changes during normal aging to pathological changes in two C. elegans models of dementia. Comparisons with models of dementia will distinguish healthy from pathological age-dependent changes. Through these studies, the contributions of specific components to functional cognition will be used to identify the best targets of therapeutic intervention to treat cognitive decline with age. PUBLIC HEALTH RELEVANCE: In our work, we propose to use the model organism C. elegans to discover genes whose changes in function are correlated with decline in cognitive ability with age. We have designed a test of long-term memory in this organism, and observe that the animals lose their ability to remember with age. Using this test and various molecular tools, we can study the genes and cells responsible for loss of memory with age and in neurodegenerative disease.