Bioanalysis Core

生物分析核心

基本信息

批准号：
10553046
负责人：
PETER D. ADAMS
金额：
$ 186.35万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553046
关键词：
Ablation Address Age Aging Architecture Atlases Biological Biological Assay Bone Marrow Brain Breast Cell Aging Cells Cellular Assay Characteristics Chromatin Collaborations Colon DNA Methylation Data Data Analyses Data Set Disease Epigenetic Process Evaluation Exhibits Female Foundations Functional disorder Future Gene Expression Genes Genetic Goals Heterogeneity Histone Deacetylase Histone Deacetylase Inhibitor Human Imaging technology In Situ Individual Inflammatory Knowledge Link Liver Longevity Maps Measurement Molecular Molecular Profiling Mouse Strains Mus Neighborhoods Organ Pharmacology Phenotype Population Research Resolution Technology Tissue atlas Tissues Vorinostat Work drinking water epigenome epigenomics genetic approach histone modification innovation male multiple omics protein biomarkers senescence telomere tissue mapping tool transcriptome transcriptomics whole genome

项目摘要

PROJECT SUMMARY Cellular senescence, characterized by stable proliferation arrest and secretion of pro-inflammatory factors, is not only a hallmark of aging, but also a key contributor to age-associated diseases in humans. As the US population is aging, there is an added urgency to gain a better understanding of cellular senescence in different tissues over the lifespan. Unfortunately, we still lack the knowledge to unambiguously define senescence at the molecular and cellular levels, due to its heterogeneous phenotypes. To address this major gap in knowledge, we propose to establish a tissue mapping center that focuses on the identification and characterization of senescent cells in healthy male and female mouse brain, bone marrow, breast, colon and liver. Our research strategy builds on recent advances in single cell epigenomics technologies that our team developed and the knowledge that senescent cells exhibit characteristic changes in the chromatin landscapes, histone modifications and expression of marker genes of cellular senescence. We will deploy cutting-edge single cell in situ and tissue dissociative multi-omic tools that have been well established in our center to produce comprehensive single cell resolution maps of the transcriptome and epigenome in male and female mouse brain, bone marrow, breast, colon and liver, and to provide qualitative and quantitative spatial maps of the normal burden of senescent cells in these vital organs, across the lifespan of two mouse strains. We will rigorously validate the newly defined senescent cell populations using pharmacologic and genetic approaches to eradicate senescent cells or suppress their inflammatory phenotype, and orthogonal state-of-the-art and conventional assays for cellular senescence. We will generate whole genome single cell DNA methylation data to link our spatial atlas to measurement of epigenetic age, a candidate predictor of beneficial versus detrimental effects of senescent cells. We expect that comprehensive single cell atlases of epigenome and transcriptome will enable us to identify and characterize cellular senescence in different tissue contexts and during aging. We expect that the planned research will provide a reference for future studies that seek to characterize and target senescent cells associated with or preceding disease in brain, bone marrow, breast, colon and liver.

项目摘要细胞衰老，其特征是稳定的增殖停滞和促炎性因素的分泌，不仅是衰老的标志，而且还是人类与年龄相关疾病的关键因素。作为美国人口正在衰老，还有一个紧迫性，可以更好地了解细胞衰老在整个生命周期内不同的组织。不幸的是，我们仍然缺乏明确定义的知识由于其异质表型，在分子和细胞水平上的衰老。解决这个专业知识差距，我们建议建立一个侧重于识别和的组织映射中心健康男性和雌性小鼠脑，骨髓，乳房，结肠和衰老细胞的表征肝。我们的研究策略以我们团队的单细胞表观基因组学技术的最新进展为基础开发以及衰老细胞在染色质中表现出特征变化的知识景观，组蛋白的修饰和细胞衰老标记基因的表达。我们将部署尖端的单细胞原位和组织解离的多摩变工具已在我们的在男性中产生转录组和表观基因组的全面单细胞分辨率图的中心和雌性小鼠脑，骨髓，乳房，结肠和肝脏，并提供定性和定量在这些重要器官中，在两只小鼠的寿命中，衰老细胞正常负担的空间图菌株。我们将使用药理学和根除衰老细胞或抑制其炎症表型和正交的遗传方法细胞衰老的最新和常规测定法。我们将生成整个基因组单细胞 DNA甲基化数据将我们的空间地图集与表观遗传时代的测量联系起来，这是候选的预测因子衰老细胞的有益与有害作用。我们期望那个全面的单元格表观基因组和转录组将使我们能够识别和表征不同的细胞衰老组织环境和衰老期间。我们希望计划的研究将为未来提供参考试图表征和靶向与疾病或先前疾病有关的衰老细胞的研究脑，骨髓，乳房，结肠和肝脏。