INTEGRATION OF DNA DAMAGE RESPONSES WITH IMMUNE DEVELOPMENT AND FUNCTION

DNA 损伤反应与免疫发育和功能的整合

基本信息

批准号：
8686595
负责人：
Jeffrey J Bednarski
金额：
$ 12.68万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-10 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686595
关键词：
Antigen Receptors Apoptosis Apoptotic Attenuated Award B Cell Proliferation B-Lymphocytes Biological Response Modifiers Cell Cycle Cell Death Cell Death Signaling Process Cell Proliferation Cell Survival Cells Cessation of life Characteristics Chromosomal translocation Clinical Cues Cytokine Receptors DNA DNA Damage DNA Sequence Rearrangement Development Development Plans Disease Down-Regulation Ensure Environment Equilibrium Event Extramural Activities Foundations Funding Gene Expression Gene Rearrangement Generations Genes Genetic Recombination Genetic Transcription Genomics Germination Goals Immune Immune response Immunologic Receptors Immunology Individual Interleukin-7 Investigation Kinetics Laboratory Research Lead Lymphocyte Malignant Neoplasms Malignant lymphoid neoplasm Mentors Modeling Pathogenesis Pathway interactions Phenotype Physiological Process Property Protein-Serine-Threonine Kinases RAG1 gene Receptor Gene Receptor Signaling Regulation Research Secondary to Signal Pathway Signal Transduction Source Surface T-Cell Receptor TNFRSF5 gene Techniques Testing Time Transactivation Work attenuation career career development cytokine endonuclease insight irradiation leukemia/lymphoma leukemogenesis metaplastic cell transformation novel nuclease prevent programs receptor repaired research study response skills therapy development tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Lymphocyte development is precisely controlled to enable generation of a diverse antigen receptor repertoire while, simultaneously, preventing deleterious events, such as translocations, which promote cellular transformation and lymphoid malignancies. These two dichotomous but interdependent processes are managed through the cooperation of diverse cellular signals, which control cell proliferation, survival, and antigen receptor assembly. We describe a novel signaling pathway in pre-B cells that is initiated by the physiologic DNA breaks generated during antigen receptor recombination. Surprisingly, our work demonstrates that DNA break-dependent signals paradoxically activate survival pathways that are important to ensure adequate time for antigen receptor gene rearrangement. However, if DNA breaks cannot be repaired, the same DNA damage responses trigger cell death to prevent translocations and protect genomic integrity. This temporal balance of survival and apoptosis is unique to physiologic DNA breaks as genotoxic insults, such as gamma irradiation, induce immediate cell death without an initial survival period. The goal of this project is to elucidate the mechanisms that coordinate survival and cell death signaling in response to DNA breaks in lymphocytes. Utilizing an experimental approach that permits isolation of DNA break signals and surface receptor signals, we propose to: 1) define the properties of physiologic DNA breaks that control survival kinetics, 2) identify the signals that regulate delayed apoptotic signaling in response to DNA breaks, and 3) define the functional integration of signals from DNA breaks and immune regulators (i.e., CD40) in the regulation of lymphocyte survival. Ultimately, this work will elucidate new signaling networks that balance survival and cell death in developing lymphocytes to ensure normal maturation and inhibit leukemogenesis. These investigations will establish the foundation for an independent scientific career focused on applying basic immunology research to the pathogenesis of clinical diseases, particularly immune deficiencies and lymphoid malignancies. The mentored period of this award will provide protect time to develop new techniques for studying DNA damage responses in lymphocytes and to acquire new skills necessary for managing a research laboratory. These tools will be essential for completion of the outlined experiments and for the germination of an independent research program. A collaborative and robust immunology research environment will help guide future research directions. This application presents a research program and a career development plan that will provide the framework and skills necessary for establishing independence and competing for extramural funding.

描述（由申请人提供）：精确控制淋巴细胞的发育以产生多样化的抗原受体库，而同时可以预防有害事件，例如易位，从而促进细胞转化和淋巴瘤恶性肿瘤。这两个二分法但相互依存的过程是通过多种细胞信号的合作来管理的，该信号控制细胞增殖，存活和抗原受体组装。我们描述了Pre-B细胞中的一种新型信号通路，该信号通路是由在抗原受体重组过程中产生的生理DNA断裂引发的。令人惊讶的是，我们的工作表明，DNA断裂信号矛盾地激活生存途径，这对于确保足够的抗原受体基因重排的时间很重要。但是，如果无法修复DNA断裂，则相同的DNA损伤反应会触发细胞死亡，以防止易位并保护基因组完整性。生存和凋亡的这种时间平衡是生理DNA的特有的，例如遗传毒性损伤，例如伽马射线，诱导没有初始生存期的立即细胞死亡。该项目的目的是阐明响应淋巴细胞中DNA断裂的生存和细胞死亡信号的机制。利用允许隔离DNA断裂信号和表面受体信号的实验方法，我们建议：1）定义控制生存动力学的生理DNA的特性，2）确定调节对DNA响应的延迟凋亡信号的信号，并定义DNA响应的响应，并定义DNA的功能范围（3））（3）定义了DNA的功能（3））（3））（3））（3）淋巴细胞存活。最终，这项工作将阐明平衡生存和细胞死亡的新信号网络发展淋巴细胞，以确保正常的成熟并抑制白血病。这些调查将为一个独立的科学生涯奠定基础，该职业专注于将基本免疫学研究应用于临床疾病的发病机理，尤其是免疫缺陷和淋巴恶性肿瘤。该奖项的指导期限将为开发新技术提供研究，以研究淋巴细胞中DNA损伤反应的新技术，并获得管理研究实验室所需的新技能。这些工具对于完成概述的实验以及独立研究计划的发芽至关重要。协作和强大的免疫学研究环境将有助于指导未来的研究方向。该应用程序提出了一项研究计划和职业发展计划，该计划将提供建立独立性和争夺壁外资金所需的框架和技能。