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：
10630928
负责人：
Jeffrey J Bednarski
金额：
$ 23.35万
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/10630928
关键词：
Antibody Repertoire 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 Replication Factor Data Defect Deubiquitinating Enzyme Development Dissociation Exposure to Fc Receptor Gene Expression Generations Genes Genetic Genotoxic Stress Germ-Line Mutation Goals Hereditary Disease Histone H2A Human Immune Immune System Diseases Immune system Immunity Immunology Impairment Investigation Knowledge Lymphopenia Mediating Molecular 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 cell growth regulation cell type congenital immunodeficiency endonuclease experimental study humoral immunity deficiency 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 ubiquitin isopeptidase

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.

项目概要先天性免疫错误为研究已识别基因在免疫系统中的作用提供了独特的机会。免疫系统的发育和功能。对这些免疫疾病的研究提供了对人类免疫的重要见解，并建立了基础和临床的基本原则免疫学。在这方面，最近在原发性乳腺癌患者中发现了 MYSM1 种系变异。免疫缺陷的特点是 T 细胞含量低、B 细胞几乎完全缺失、低丙种球蛋白血症、以及对遗传毒性物质的敏感性增加。 MYSM1 在免疫发育和细胞中的作用对 DNA 损伤的反应仍然是一个关键的知识空白。 MYSM1 缺乏会导致 DNA 增加在没有暴露于 DNA 损伤剂的情况下，损伤信号，尤其是 B 细胞中的损伤信号。早期期间发育过程中，B 细胞（和 T 细胞）会产生 DNA 断裂来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以识别各种不同的病毒至关重要。病原体。在初步实验中，我们发现，为了响应这些程序化的 DNA 断裂， MYSM1 导致持续的 DNA 损伤信号传导，包括激活细胞死亡程序，从而损害 B细胞成熟。我们的目标是确定 MYSM1 调节细胞反应的机制 DNA 损伤并协调 B 细胞发育。我们建议 MYSM1 函数终止 DNA 断裂修复后的 DNA 损伤反应，这种活性对于抑制细胞死亡至关重要促进 B 细胞持续发育的途径。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。了解这些信号免疫细胞中的直接 DNA 损伤程序对于阐明初级免疫机制至关重要缺陷并优化治疗方法。这些研究将建立一个新的灭活范例 DNA 损伤反应将揭示改善患者临床管理的新机会 MYSM1 缺陷以及其他 DNA 损伤途径异常的患者。