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Role of ARID3a in aging human hematopoietic progenitor cells

ARID3a在人类造血祖细胞衰老中的作用

基本信息

批准号：
10443889
负责人：
Michelle Leigh Ratliff
金额：
$ 23.97万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443889
关键词：
ARID3A gene ATAC-seq Adult Affect Age Age-Years Aging Autoantibodies Binding Blood Blood Cells Cells ChIP-seq Complex DNA-Binding Proteins Data Defect Development Dominant-Negative Mutation Elderly Epigenetic Process European Exhibits Flow Cytometry Frequencies Future Gene Expression Gene Expression Regulation Genes Goals Hematopoiesis Hematopoietic Hematopoietic stem cells Human Immune Immune response Immunization Impairment In Vitro Individual Influenza Innate Immune Response Keyhole Limpet Hemocyanin Knockout Mice Lead Lymphoid Multipotent Stem Cells Mus Myelogenous Myeloid Progenitor Cells Pathway interactions Patients Play Population Population Study Process Production Regimen Regulation Reporting Role Streptococcus pneumoniae Systemic Lupus Erythematosus Techniques Training Transgenic Mice Vaccination age related aged base cell type chromatin remodeling differential expression hematopoietic stem cell differentiation hematopoietic stem cell expansion human subject humanized mouse immune function immunosenescence improved in vivo in vivo Model insight new therapeutic target overexpression pathogen peripheral blood phenotypic data progenitor response self-renewal senescence small hairpin RNA therapeutic target transcription factor transcriptome transcriptome sequencing

项目摘要

Project Summary Human hematopoiesis is a complex, dynamic process that requires intricate regulation of multiple gene pathways involved in lineage commitments, leading to development of multiple mature blood cell types. Multiple studies in mice and humans report age-related defects in early hematopoiesis and functions defects in the mature aged immune cell populations, which leads to impaired immune responses to pathogens. These defects are especially important because population studies estimate that nearly 40% of European and US populations will be over 60 years of age by 2050. Previous studies in our lab indicate that loss of expression of the DNA-binding protein ARID3a leads to hematopoietic developmental skewing away from lymphoid lineage progenitors, indicating that ARID3a is important for normal hematopoiesis. Preliminary data from aged human peripheral blood shows decreased frequency of ARID3a-expressing hematopoietic stem cells (HSCs), leading to decreased numbers of multipotent progenitors and multi-lymphoid progenitors, but no alterations in numbers of myeloid progenitor cells when compared to healthy young peripheral blood. The proposed studies seek to expanded the preliminary phenotypical data of ex vivo young and aged human peripheral blood hematopoietic progenitor cells for statistical significance, evaluate and compare developmental potential of young ARID3a- expressing, young ARID3a-deficient and aged HSCs in vitro and in vivo. We will further examine the gene expression differences between young and old, as well as between ARID3a expressing and ARID3a deficient HSCs by RNA-seq. Differentially expressed genes will be further analyzed for ARID3a binding and chromatin remodeling by ChIP-seq and ATAC-seq analyses. These sequencing techniques will be the focus of the training portion of this proposal. Finally, we will evaluate the capacity of young ARID3a-expressing, young ARID3a-deficient, and old HSC engrafted humanized mice to mount immune responses to immunization with PC-KLH and survival following inoculation with S. pneumoniae. The overall goal of the proposed studies is to determine the effect of ARID3a expression in HSCs on immunosenescence and innate immune responses. Completion of these studies will stratify HSCs based on ARID3a expression, identify ARID3a-regulated genes important for aging, and identify potential therapeutic targets for improving immunological function in elderly individuals.

项目摘要人类的造血是一个复杂的动态过程，需要复杂的多基因调控。参与血统承诺的途径，导致多种成熟血细胞类型的发展。在小鼠和人类中的多项研究报告了早期造血中与年龄相关的缺陷和成熟的老年免疫细胞群，导致对病原体的免疫反应受损。这些缺陷尤其重要，因为人口研究估计，近40%的欧洲和美国到2050年，人口将超过60岁。我们实验室以前的研究表明，表达的缺失 DNA结合蛋白ARID3a导致造血发育偏离淋巴系这表明ARID3a对正常的造血起着重要作用。来自老年人的初步数据外周血中表达ARID3a的造血干细胞(HSCs)频率降低，导致多能祖细胞和多淋巴祖细胞数量减少，但数量没有变化当与健康的年轻外周血相比时，髓系祖细胞的数量。拟议的研究旨在体外扩增青年和老年人外周血造血细胞的初步表型数据祖细胞的统计学意义，评估和比较幼年ARID3a的发育潜力在体外和体内表达年轻的ARID3a缺陷的和老化的HSCs。我们将进一步检测该基因 ARID3a在青年和老年人以及ARID3a表达和缺失之间的表达差异用RNA-seq.差异表达的基因将进一步分析ARID3a结合和染色质通过CHIP-SEQ和ATAC-SEQ分析进行重塑。这些测序技术将是本提案的培训部分。最后，我们将评估年轻的ARID3a表达的能力， ARID3a缺陷和老年HSC移植人化小鼠以增强对免疫的免疫应答 PC-KLH和肺炎链球菌接种后的存活。拟议研究的总体目标是确定ARID3a在HSC中的表达对免疫衰老和先天免疫反应的影响。这些研究的完成将根据ARID3a的表达对HSC进行分层，识别ARID3a调节的基因对衰老的重要性，并确定改善老年人免疫功能的潜在治疗靶点个人。