MYSM1-dependent DNA damage responses in early B cell development

早期 B 细胞发育中 MYSM1 依赖性 DNA 损伤反应

基本信息

批准号：
10527156
负责人：
Jeffrey J Bednarski
金额：
$ 19.69万
依托单位：
WASHINGTON UNIVERSITY
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：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527156
关键词：
Antibodies Antigen Receptors B-Cell Development B-Lymphocytes Catalytic Domain Cell Cycle Arrest Cell Death Cell Maturation Cell Survival Cells Chromatin Clinical Immunology Clinical Management DNA DNA Damage DNA Double Strand Break DNA biosynthesis Data Defect Deubiquitinating Enzyme Development Dissociation Exposure to Fc Receptor Generations Genes Goals Hereditary Disease Histone H2A Human Immune Immune System Diseases Immune system Immunity Immunology Impairment Investigation Knowledge Lymphopenia Mediating Molecular Molecular Genetics Mutagens Mutate Mutation Pathway interactions Patients Phosphorylation Site Radiation Tolerance Receptor Gene Resolution Role Signal Transduction Site T-Lymphocyte TP53 gene Testing Therapeutic Intervention Ubiquitin Ubiquitination Variant attenuation base cell growth regulation cell type congenital immunodeficiency endonuclease experimental study genotoxicity hypogammaglobulinemia immune system function immunological diversity improved insight irradiation novel p53-binding protein 1 pathogen programs reconstitution recruit repaired response stem cells transcription factor treatment optimization

项目摘要

PROJECT SUMMARY Inborn errors of immunity provide unique opportunities to investigate the role of identified genes in the development and function of the immune system. Investigation of these immune disorders has provided important insights into human immunity and has established fundamental principles of basic and clinical immunology. In this regard, germline variants in MYSM1 have recently been identified in patients with primary immune deficiency characterized by low T cells, near complete absence of B cells, hypogammaglobulinemia, and increased sensitivity to genotoxic agents. The role of MYSM1 in immune development and in cellular response to DNA damage remain a critical knowledge gap. Deficiency of MYSM1 results in increased DNA damage signals, particularly in B cells, in the absence of exposure to DNA damaging agents. During early development, B cells (and T cells) generate DNA breaks to assembly the genes that encode their antibody receptors. These DNA breaks are essential for creating the diversity of the immune system to recognize various pathogens. In preliminary experiments, we find that, in response to these programmed DNA breaks, loss of MYSM1 results in persistent DNA damage signaling, including activation of cell death programs, which impairs B cell maturation. Our goal is to determine the mechanism of MYSM1 in regulation of cellular responses to DNA damage and in coordination of B cell development. We propose that MYSM1 functions to terminate DNA damage responses after DNA break repair and that this activity is critical for suppressing cell death pathways to promote continued B cell development. We will define the role of MYSM1 in DNA damage signaling in early B cells and will determine the mechanisms that regulate MYSM1 activity. Understanding the signals that direct DNA damage programs in immune cells is essential for elucidating mechanisms of primary immune deficiency and for optimizing treatment approaches. These studies will establish a new paradigm for inactivating DNA damage responses and will reveal new opportunities to improve clinical management of patients with MYSM1 deficiency as well as patients with abnormalities in other DNA damage pathways.

项目摘要先天免疫错误为研究已鉴定基因的作用提供了独特的机会免疫系统的开发和功能。对这些免疫疾病的调查已提供对人类免疫力的重要见解，并建立了基本和临床的基本原理免疫学。在这方面，最近在原发性患者中发现了MySM1的种系变异免疫缺陷为低T细胞的特征，几乎完全不存在B细胞，低磁性血症，并提高对遗传毒性剂的敏感性。 MySM1在免疫发育和细胞中的作用对DNA损害的反应仍然是一个关键的知识差距。 MYSM1的缺乏导致DNA增加损伤信号，特别是在B细胞中，没有暴露于DNA损伤药物的情况下。在早期开发，B细胞（和T细胞）会产生DNA破裂以组装编码其抗体的基因受体。这些DNA断裂对于创造免疫系统的多样性至关重要病原体。在初步实验中，我们发现，在响应这些编程的DNA断裂时， MYSM1导致持续的DNA损伤信号传导，包括激活细胞死亡程序，这会损害 B细胞成熟。我们的目标是确定MySM1在调节细胞反应中的机制进行DNA损伤和B细胞发育的协调。我们建议mysm1功能终止 DNA断裂修复后的DNA损伤反应，此活动对于抑制细胞死亡至关重要促进持续B细胞发展的途径。我们将定义MySM1在DNA损伤信号传导中的作用在早期B细胞中，将确定调节MySM1活性的机制。了解信号免疫细胞中的直接DNA损伤程序对于阐明原发性免疫的机制至关重要缺乏和优化治疗方法。这些研究将建立一个新的范式灭活 DNA损伤反应，并将揭示新的机会，以改善患者的临床管理 MYSM1缺乏以及其他DNA损伤途径异常的患者。