Exploring the Role of Transcriptome Variation in Cognitive Decline

描述（由申请人提供）：在本项目中，我们将研究人脑组织的转录组，以解析导致衰老人脑认知能力下降过程的RNA转录本和功能变体。我们使用下一代RNA测序来创建这些转录组的方法将允许对大脑转录调控的复杂性进行无与伦比的透视，大脑是一种具有最多样化的可变剪接转录本和非编码RNA分子内容之一的组织，其中许多可能以前没有被发现。此外，相同受试者的全基因组基因型数据的可用性为我们提供了探索遗传对RNA表达的影响的独特机会。因此，我们不仅可以深入了解衰老人脑的转录组多样性，还可以了解与临床认知障碍相关的遗传变异对人脑产生功能性影响的方式。! ! 公共卫生相关性：这项研究的目的是了解大脑组织中的哪些分子参与了老年人的认知能力下降。了解这些分子如何与衰老和人类认知功能的遗传风险相关，将使研究人员能够更好地了解认知衰退和认知疾病的发病，如阿尔茨海默病（AD）。这可能有助于开发临床测试，可以预测谁有患AD的风险，并开发新的治疗方法来延迟或预防认知能力下降和AD的发作。

DESCRIPTION (provided by applicant): In this project, we will investigate the transcriptomes of a human brain tissue to resolve RNA transcripts and functional variants that contribute to the process of cognitive decline in the aging human brain. Our approach using next generation RNA sequencing to create these transcriptomes will allow an unparalleled perspective on the complexity of transcriptional regulation of the brain, which is a tissue with one of the most diverse content of alternatively spliced transcripts and non-coding RNA molecules, many of which may not have been previously discovered. Further, the availability of genome-wide genotype data on the same subjects gives us a unique opportunity to explore the genetic effects on RNA expression. Thus, we may gain insight not only into the transcriptome diversity of the aging human brain but also into the manner in which genetic variation associated with clinically impaired cognition exert a functional consequence on the human brain. ! ! PUBLIC HEALTH RELEVANCE: The goal of this proposal is to understand which molecules of a brain tissue are involved in the cognitive decline in older individuals. In understanding how these molecules relate to genetic risk for aging and human cognitive function will allow investigators to better understand the onset of cognitive decline and diseases of cognition, such as Alzheimer's disease (AD). This may help to develop clinical tests that may be able to predict who is at risk of developing AD and to develop new treatments to delay or prevent onset of cognitive decline and AD.