Molecular mechanisms of aging and accelerated aging in the human brain

总结。此建议是对PAR-21-038：Stephen I.Katz早期调查者研究的回应 格兰特项目。衰老是导致认知缺陷和神经退行性变的主要危险因素 疾病。了解大脑老化和加速脑老化的确切分子机制可以导致 有助于开发新的干预措施来延缓或潜在地逆转大脑衰老。环境因素 包括病毒感染(如导致新冠肺炎大流行的SARS-CoV-2病毒)一直是 研究表明，这与认知能力下降和大脑加速老化有关。然而，确切的分子 环境因素，特别是新冠肺炎对大脑老化影响的潜在机制仍然存在 未知。我们的长期目标是确定导致大脑加速衰老的关键因素，以便治疗 可以被开发来延缓或逆转大脑衰老。这项提议的总体目标是识别基因和 导致新冠肺炎患者脑老化和加速脑老化的基因表达调控。上一首 我们小组的研究表明，许多microRNAs(MiRNAs)，即诱导 一个精心安排的基因表达调控，在衰老的小鼠脑中差异表达并调节 衰老。基于这些数据和我们最近发表的批量RNA测序研究表明，分子 新冠肺炎患者脑老化的特征，我们的中心假设是失调的基因和miRNA 表情是加速大脑老化的一个重要方面。先前使用微阵列和整体RNA进行的研究 测序方法表明，衰老在人类额叶皮质中诱导了不同的分子特征。 虽然已经在人类额叶皮质中发现了层次丰富的表达特征，但空间 衰老的分子特征在很大程度上仍不清楚。在这里，我们将利用最先进的空间 转录学技术分析健康人一生中的额叶皮质切片， 以及新冠肺炎患者(和适当的对照组)的额叶皮质切片，以识别空间上不同的 衰老调节的转录转录变化。我们将研究衰老调节基因对细胞的影响 体外衰老试验。更好地理解衰老调控基因的调控机制 为了更好地表达miRNA，我们将测量健康个体在不同寿命和新冠肺炎中的miRNA表达 在类似的额叶皮质切片上的病例，我们将确定候选miRNAs的衰老调节的mRNA靶标。 最后，我们将使用体外实验和小鼠体内实验来测试miRNAs加速和延缓衰老的潜力。 模特们。这些研究预计将产生重大影响，因为它们将确定 延缓或逆转大脑衰老和衰老相关神经病理学的治疗方法的发展。这项建议是 与公共卫生高度相关，与NIA促进对老龄化原因的了解的使命高度相关 治疗过程和与年龄相关的疾病，以延长健康寿命。

SUMMARY. This proposal is in response to PAR-21-038: Stephen I. Katz Early Stage Investigator Research Project Grant. Aging is a major risk factor for the development of cognitive deficits and neurodegenerative diseases. Understanding the exact molecular mechanisms of brain aging and accelerated brain aging can lead to the development of novel interventions to delay or potentially reverse brain aging. Environmental factors including viral infections (such as SARS-CoV-2, the virus that caused the COVID-19 pandemic) have been shown to be associated with cognitive decline and accelerated brain aging. However, the exact molecular mechanisms underlying the effects of environmental factors, and specifically COVID-19, on brain aging remain unknown. Our long-term goal is to identify key factors that induce accelerated brain aging, so that therapeutics can be developed to delay or reverse brain aging. The overall objective of this proposal is to identify genes and regulators of gene expression that cause brain aging and accelerated brain aging in COVID-19 patients. Previous research from our group showed that many microRNAs (miRNAs), which are small non-coding RNAs that induce an orchestrated regulation of gene expression, are differentially expressed in the aged mouse brain and regulate aging. Based on those data and our recently published bulk RNA sequencing studies showing molecular signatures of brain aging in COVID-19 patients, our central hypothesis is that dysregulated gene and miRNA expression is an important facet of accelerated brain aging. Previous studies using microarray and bulk RNA sequencing approaches showed that aging induces distinct molecular signatures in the human frontal cortex. While layer enriched expression signatures have been identified in the human frontal cortex, the spatial topography of molecular signatures of aging remain largely unknown. Here, we will utilize state-of-the-art spatial transcriptomic technologies to analyze human frontal cortex sections from healthy individuals across lifespan, as well as frontal cortex sections from COVID-19 patients (and appropriate controls) to identify spatially distinct aging-regulated transcriptomic changes. We will investigate the effects of aging-regulated genes on cellular senescence using in vitro assays. To better understand regulatory mechanisms of aging-regulated gene expression, we will measure the expression of miRNAs in healthy individuals across lifespan and COVID-19 cases on similar frontal cortex sections and we will identify aging-regulated mRNA targets for candidate miRNAs. Finally, we will test the potential of miRNAs to accelerate and delay aging using in vitro assays and in vivo mouse models. These studies are expected to have a significant impact as they will determine novel targets for the development of therapeutics to delay or reverse brain aging and aging-related neuropathology. This proposal is highly relevant to public health and to the NIA’s mission of advancing knowledge on the causes of aging processes and age-associated diseases to extend healthy lifespan.