Molecular mechanisms of aging and accelerated aging in the human brain

人脑衰老和加速衰老的分子机制

• 批准号: 10713873
• 负责人: Maria Mavrikaki
• 金额: $ 84.2万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713873
• 关键词: 2019-nCoV; Acceleration; Adult; Age; Aging; Autopsy; Binding Sites; Bioinformatics; Biological Assay; Brain; COVID-19; COVID-19 impact; COVID-19 pandemic; COVID-19 patient; Cell Aging; Cognition; Cognitive deficits; Coronavirus Infections; Data; Development; Disease; Environmental Risk Factor; Functional disorder; Funding Opportunities; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Human; Impaired cognition; In Vitro; Individual; Intervention; Knowledge; Longevity; Luciferases; Maps; Measures; Messenger RNA; MicroRNAs; Mission; Molecular; Molecular Profiling; Mus; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Normal tissue morphology; Phenotype; Play; Process; Public Health; Publishing; Recording of previous events; Regulator Genes; Reporter; Research; Research Personnel; Research Project Grants; Risk Factors; Site-Directed Mutagenesis; Small RNA; Spatial Distribution; Technology; Testing; Therapeutic; Tissues; Untranslated RNA; Validation; Ventilator; Virus; Virus Diseases; adeno-associated viral vector; age effect; aged; aging brain; cell type; cognitive function; differential expression; frontal lobe; in vitro Assay; in vivo; induced pluripotent stem cell; mouse model; neuropathology; new therapeutic target; novel; prevent; promoter; response; senescence; severe COVID-19; single-cell RNA sequencing; therapeutic development; transcriptome sequencing; transcriptomics

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.

概括。该建议是对PAR-21-038的回应：Stephen I. Katz早期研究员研究 项目赠款。衰老是认知缺陷和神经退行性发展的主要危险因素 疾病。了解大脑衰老和加速大脑衰老的确切分子机制可以引导 开发新的干预措施以延迟或可能逆转大脑衰老。环境因素 包括病毒感染（例如SARS-COV-2，引起Covid-19大流行的病毒）已是 证明与认知能力下降和加速脑衰老有关。但是，确切的分子 环境因素，特别是共同-19对脑衰老的影响的基础机制仍然存在 未知。我们的长期目标是确定引起加速大脑衰老的关键因素，以便治疗 可以开发以延迟或逆转大脑衰老。该提案的总体目的是确定基因和 在199例患者中导致脑衰老和加速脑老化的基因表达调节剂。以前的 我们小组的研究表明，许多影响的无编码RNA的许多microRNA（miRNA）会影响 在老年小鼠大脑中，精心策划的基因表达调节表达不同，并调节 老化。根据这些数据，我们最近发表的大量RNA测序研究显示了分子 在199例患者中，脑老化的特征是我们的中心假设是基因和miRNA失调 表达是加速大脑衰老的重要方面。先前使用微阵列和大量RNA的研究 测序方法表明，衰老会在人额叶皮层中诱导不同的分子特征。 虽然在人额皮层中已经确定了层富集的表达特征，但空间 衰老的分子特征的地形在很大程度上未知。在这里，我们将利用最先进的空间 转录组技术以分析来自健康个体的人类额叶皮层切片， 以及来自COVID-19患者（和适当对照组）的额叶皮层切片，以识别空间不同的 衰老调节的转录组变化。我们将研究衰老调节基因对细胞的影响 使用体外测定法。更好地了解衰老调节基因的调节机制 表达，我们将测量整个生命周期和Covid-19的健康个体中miRNA的表达 类似的额叶皮层切片的病例，我们将确定候选miRNA衰老调节的mRNA靶标。 最后，我们将测试miRNA的潜力，使用体外测定和体内小鼠加速和延迟衰老 型号。预计这些研究将产生重大影响，因为它们将确定 理论的发展延迟或逆转大脑衰老和与衰老有关的神经病理学。该提议是 与公共卫生高度相关以及NIA的使命是促进有关衰老原因的知识 过程和与年龄相关的疾病延长健康的寿命。