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

灵长类动物以其漫长而缓慢的生活史和延长的寿命而闻名，这一趋势在人类身上被夸大了。这种延长寿命的影响可以在整个身体观察到，包括大脑。虽然大脑老化的一般模式在灵长类动物中是保守的，但物种内和物种之间大脑老化的速度存在明显的差异。此外，人类可能更容易患上与衰老过程相关的神经退行性疾病；然而，目前尚不清楚是什么分子机制使这种变异成为可能或塑造了这种变异。这个博士论文项目描述了非人灵长类动物海马体衰老的分子特征，以确定灵长类动物大脑衰老的保守和衍生特征，并促进我们对人类潜在的进化差异的理解，这些差异可能会增加我们对年龄相关脑病的易感性。该项目扩大了研究生和本科生的参与范围，包括来自STEM代表性不足群体的学生，提供生物信息学和基因组分析方面的培训、指导和研究经验。此外，随着全球预期寿命的增加，该项目通过在分子水平上提高我们对衰老过程的理解，并为未来与衰老相关的研究提供有价值的分子数据集，解决了一个特定的全球健康问题。本研究的中心假设是，基因调控通过调节灵长类动物的环境和生物之间的相互作用来塑造海马体的衰老。目的1利用已有的生物样本，研究恒河猴海马区基因在整个生命周期的表达。然后将这些数据与之前生成的匹配DNA甲基化数据相结合，以确定可能调节海马体中年龄相关基因表达的差异甲基化区域。目的2鉴定恒河猴海马区表达的microRNAs，并研究其在整个生命周期中的表达模式。然后将这些数据与来自目标1的匹配的基因表达数据相结合，以确定候选的miRNA-mRNA对和网络。为了满足这些目标，我们分别使用RNAseq和Small RNAseq为海马区样本生成匹配的mRNA和miRNA数据并进行分析。重要的是，这一数据集包括男性和女性以及一系列年龄。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.