Doctoral Dissertation Research: Molecular signatures of aging in the primate hippocampus

博士论文研究：灵长类海马衰老的分子特征

• 批准号: 2217961
• 负责人: Kirstin Sterner
• 金额: $ 2.19万
• 依托单位: University of Oregon Eugene
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2217961&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Research; Molecular; signatures

Primates are notable for their long, slow life histories and extended lifespans, a trend exaggerated in humans. The effects of this prolonged lifespan can be observed across the body, including the brain. While general patterns of brain aging are conserved among primates, there is clear variation in the pace of brain aging within and between species. In addition, humans are potentially more vulnerable to neurodegenerative diseases associated with the aging process; however, it is not clear what molecular mechanisms enable or shape this variation. This doctoral dissertation project characterizes molecular signatures of aging in the hippocampus of a non-human primate to identify conserved and derived features of primate brain aging and advance our understanding of potential evolved differences in humans that may increase our susceptibility to age-related brain disease. The project broadens the participation of graduate and undergraduate students, including those from underrepresented group in STEM, providing training, mentoring, and research experiences in bioinformatics and genomic analyses. In addition, with life expectancy increasing globally, this project addresses a specific global health concern by improving our understanding of the aging process at the molecular level and by contributing a valuable molecular dataset for future aging-related research.The central hypothesis of this research is that gene regulation shapes hippocampal aging by mediating the interaction between a primate’s environment and biology across its lifespan. Objective 1 characterizes gene expression in the hippocampus of rhesus macaques across the lifespan using existing biosamples. These data are then integrated with previously generated matched DNA methylation data to identify differentially methylated regions that may regulate the expression of age-associated genes in the hippocampus. Objective 2 identifies microRNAs expressed in the hippocampus of rhesus macaques and characterizes their patterns of expression across the lifespan. These data are then integrated with matched gene expression data from Objective 1 to identify candidate miRNA-mRNA pairs and networks. To meet these objectives, matched mRNA and miRNA data are generated and analyzed for hippocampus samples using RNAseq and small RNAseq respectively. Importantly, this dataset includes both males and females and a range of ages.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

灵长类动物以其悠久而缓慢的生活历史和延长的寿命而着称，这是人类夸大的趋势。可以在包括大脑在内的整个体内观察到这种延长寿命的影响。虽然脑老化的一般模式在原发性中是保守的，但物种内部和物种之间的大脑衰老速度有明显的变化。此外，人类可能更容易受到与衰老过程相关的神经退行性疾病的影响。但是，尚不清楚哪种分子机制可以启用或塑造这种变异。该博士学位论文项目是特征在非人类灵长类动物海马中衰老的分子特征，以识别原发性脑老化的保守和衍生特征，并促进我们对人类潜在进化差异的理解，这些差异可能会增加我们对年龄相关脑疾病的易感性。该项目扩大了研究生和本科生的参与，包括来自STEM的代表性不足的小组，提供了生物信息学和基因组分析的培训，心理和研究经验。此外，随着全球预期寿命的增加，该项目通过提高我们对分子水平的衰老过程的理解以及为未来衰老相关的研究贡献有价值的分子数据集来解决特定的全球健康问题。这项研究的中心假设是，基因调节塑造了河马衰减，从而使河马衰减介导了跨越的环境和生物学之间的相互作用。目标1表征了使用现有的生物样本在整个寿命的恒河猕猴海马中的基因表达。然后将这些数据与先前生成的匹配的DNA甲基化数据集成在一起，以鉴定可能调节海马中与年龄相关基因表达的不同甲基化区域。目标2标识了猕猴的海马中表达的microRNA，并表征了它们在整个寿命中的表达方式。然后将这些数据与来自目标1的匹配基因表达数据集成在一起，以识别候选miRNA-MRNA对和网络。为了达到这些目标，分别使用RNASEQ和小RNASEQ生成了匹配的mRNA和miRNA数据，并分析了海马样品。重要的是，该数据集包括男性和女性以及一系列年龄。该奖项反映了NSF的法定任务，并通过使用基金会的知识分子优点和更广泛的影响审查标准来评估被认为是宝贵的支持。