Igh locus function in immunosenescent mice

免疫衰老小鼠中的 Igh 基因座功能

• 批准号: 10303603
• 负责人: Amy L Kenter
• 金额: $ 23.45万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-11 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303603
• 关键词: 2019-nCoV; 3-Dimensional; Adult; Age; Antibody Repertoire; Antibody Response; B-Cell Development; B-Lymphocytes; Binding; Biological Assay; Biological Models; Bone Marrow; COVID-19; COVID-19 mortality; COVID-19 susceptibility; Cell Line; Cell physiology; Cells; ChIP-seq; Chromatin; Clinical; Communicable Diseases; Coronavirus; DNA; Data; Disease; Elements; Enhancers; Epigenetic Process; Exons; Family; Frequencies; Functional disorder; Generations; Genes; Genetic Recombination; IGH@ gene cluster; Image; Immune; Immune response; Immune system; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunoglobulins; Impairment; Individual; Infectious Agent; Intervention; Light; Link; Lymphopoiesis; Mature B-Lymphocyte; Mediating; Molecular Conformation; Mus; Nucleic Acid Regulatory Sequences; Patients; Peripheral; Predisposition; Publishing; Regulatory Element; Resolution; Series; Site; TimeLine; V(D)J Recombination; Viral; adaptive immune response; age related; aged; cell age; helix-loop-helix protein E47; human old age (65+); immunosenescence; insight; member; mouse model; pandemic disease; pathogen; progenitor; promoter; response; senescence

ABSTRACT COVID-19 (coronavirus infectious disease 19) is now a global pandemic with over 49.1 million cases to date. COVID-19 is caused by severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, a member of the coronavirus family. It is striking that eighty percent of COVID-19 related deaths occur in patients aged 65 and over. Immune responses of aged adults undergo immunosenescence which expresses with multiple age dependent changes. Immune senescence is linked to restricted Ig repertoire formation and susceptibility to a variety of virally induced diseases. Older individuals are particularly vulnerable to a range of new and emerging infectious agents perhaps as a result of a less diverse antibody repertoire. However, to identify clinical interventions that mitigate the effects of immunosenescence it is critical to characterize the underlying environmental and cell intrinsic mechanisms leading to the muted adaptive immune responses. Here we propose an exploratory series of studies to examine the pre-selected Ig repertoire in early and mature B cells in young and aged mice to establish whether repertoire deficiencies observed in peripheral B cells of aged individuals originate, at least in part, from impaired V(D)J recombination, class switch recombination, locus conformation and/or Igh enhancer function. Results obtained from this exploratory project will shed light on whether a) limited Ig repertoire diversification results from impaired Igh locus function during V(D)J recombination and class switch recombination, and b) whether Igh locus dysfunction is cell intrinsic.

摘要 COVID-19（冠状病毒感染性疾病19）现在是一种全球大流行病， 约会COVID-19是由严重急性呼吸道综合征（SARS）-冠状病毒（CoV）-2引起的， 冠状病毒家族令人震惊的是，80%的COVID-19相关死亡发生在患者身上， 65岁及以上老年人的免疫应答经历免疫衰老， 多种年龄依赖性变化。免疫衰老与限制性IG库形成有关， 对各种病毒引起的疾病的易感性。老年人特别容易受到 一系列新的和正在出现的感染因子可能是由于抗体库的多样性较低。 然而，为了确定减轻免疫衰老影响的临床干预措施， 表征潜在的环境和细胞内在机制，导致静音适应 免疫反应。在这里，我们提出了一个探索性的一系列研究，以检查预先选定的IG 年轻和老年小鼠早期和成熟B细胞的谱系以确定谱系是否缺陷 在老年人的外周B细胞中观察到，至少部分来源于受损的V（D）J 在一些实施方案中，IgH增强子的功能可以是基因座重组、类别转换重组、基因座构象和/或IgH增强子功能。结果 从这个探索性项目中获得的信息将揭示a）有限的IG库多样化 由V（D）J重组和类别转换重组期间Igh基因座功能受损引起，和 B）Igh基因座功能障碍是否是细胞内在的。