Pioneer transcription factors in aging and neurodegeneration

衰老和神经退行性疾病中的先驱转录因子

基本信息

批准号：
10276285
负责人：
Ashley E Webb
金额：
$ 44.97万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10276285
关键词：
ATAC-seq Ablation Address Aging Alzheimer&apos s Disease Animal Model Biological Assay Brain Caenorhabditis elegans Cell physiology Cells Cellular Stress ChIP-seq Chromatin Chromatin Remodeling Factor Data Disease Disease Progression Etiology FOXO3A gene Family Future Gene Expression Genes Genetic Transcription Genomics Goals Health Homeostasis Human Individual Insulin Intervention Invertebrates Lead Link Longevity Mediating Meta-Analysis Metabolism Mus Nature Nerve Degeneration Neurodegenerative Disorders Pathology Pathway interactions Physiological Population Publishing Quality Control Rodent Role Signal Transduction Single Nucleotide Polymorphism Site Testing Time Tissues Transcription Factor AP-1 Work age effect age related aging brain aging population biological adaptation to stress chromatin remodeling epigenomics functional genomics genome-wide healthy aging improved induced pluripotent stem cell insight multiple omics nerve stem cell preservation prevent programs stem cell homeostasis stem cell model therapeutic candidate therapeutic target transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY A number of transcriptional regulators have been found to regulate the hallmarks of aging. In previous work, we found that the FOXO family of transcriptional regulators, which have been implicated in healthy aging across species, directly regulate a conserved network of target genes. In mice, FOXOs are central regulators of stem cell homeostasis during aging and are critical for tissue integrity. In humans, SNPs in the FOXO3 locus have been linked to longevity, and the upstream regulator of FOXO’s, insulin/IGF signaling must be tightly regulated to preserve healthy aging. Yet, we still lack an understanding of how FOXOs function at the chromatin level, and how their activity is altered during aging and in the context of neurodegeneration. In preliminary work, we identified for the first time the direct network of FOXO3 targets in human cells, and found that FOXOs function as pioneer factors to deploy a secondary network of transcriptional regulators to extend their target gene network. Here, we will address this critical question of the mechanisms underlying the pioneer activity, its heterogeneous nature, and how it changes in the context of aging and Alzheimer’s Disease. Completion of this work will reveal the chromatin-level changes that influence the activity of factors that counter aging and neurodegeneration, which may lead to strategies to improve associated pathologies.

项目概要在之前的工作中，已经发现许多转录调节因子可以调节衰老的特征。我们发现转录调节因子 FOXO 家族与健康衰老有关在小鼠中，FOXO 是中央调节因子，可跨物种直接调节保守的靶基因网络。 FOXO3 基因座中的单核苷酸多态性 (SNP) 影响衰老过程中干细胞的稳态，对人类组织完整性至关重要。与长寿有关，FOXO 的上游调节因子胰岛素/IGF 信号传导必须紧密结合然而，我们仍然不了解 FOXO 的功能。染色质水平，以及它们的活性在衰老过程中和神经退行性变的情况下如何改变。前期工作中，我们首次鉴定了人类细胞中FOXO3靶标的直接网络，并发现 FOXO 充当部署转录调节子二级网络以扩展在这里，我们将解决先驱者机制的关键问题。活性、其异质性，以及它在衰老和阿尔茨海默病的背景下如何变化。这项工作的完成将揭示染色质水平的变化，这些变化影响反作用因子的活性衰老和神经退行性变，这可能会导致改善相关病理的策略。