Igh locus function in immunosenescent mice

免疫衰老小鼠中的 Igh 基因座功能

基本信息

批准号：
10427437
负责人：
Amy L Kenter
金额：
$ 19.45万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2021-06-11 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427437
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 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

项目摘要

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.

抽象的 COVID-19（冠状病毒传染病 19）现已成为全球大流行病，已有超过 4910 万例病例日期。 COVID-19 是由严重急性呼吸综合征 (SARS)-冠状病毒 (CoV)-2 引起的，其成员之一冠状病毒家族的成员。令人惊讶的是，百分之八十的 COVID-19 相关死亡发生在患者身上 65岁及以上。老年人的免疫反应经历免疫衰老，其表达为多种年龄相关的变化。免疫衰老与 Ig 库形成受限有关对多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多样性较低的结果。然而，为了确定减轻免疫衰老影响的临床干预措施，至关重要的是表征导致适应性减弱的潜在环境和细胞内在机制免疫反应。在这里，我们提出了一系列探索性研究来检查预先选择的 Ig 年轻和老年小鼠的早期和成熟 B 细胞的谱系以确定是否存在谱系缺陷在老年人的外周 B 细胞中观察到，至少部分源自受损的 V(D)J 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结果将揭示 a) 是否有限的 Ig 库多样化 V(D)J 重组和类别转换重组期间 Igh 基因座功能受损的结果，以及 b) Igh 基因座功能障碍是否是细胞内在的。