The role of Notch signaling in human natural killer cell functional maturation

Notch信号在人类自然杀伤细胞功能成熟中的作用

基本信息

批准号：
9921194
负责人：
Ansel Peter Nalin
金额：
$ 3.97万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9921194
关键词：
Acute Myelocytic Leukemia Address Adoptive Transfer Allogenic Antigens Aryl Hydrocarbon Receptor Autologous Bioinformatics Cell Maturation Cell physiology Cells Cellular biology Cellular immunotherapy Clinical Coculture Techniques Complement Data Dendritic Cells Development Disease Exposure to Gene Targeting Genes Genetic Transcription Goals Hematopoietic Stem Cell Transplantation Human Immune Immune response Immune system Immunologic Surveillance Immunology Impairment In Vitro Innate Immune Response Interferon Type II Knowledge Laboratories Large granular lymphocyte Lymphoid Tissue Malignant Neoplasms Mediating MicroRNAs Mus Natural Killer Cells Notch Signaling Pathway Pathway interactions Patients Phenotype Physiological Play Process Publishing Receptor Activation Regulation Reporting Role Signal Pathway Signal Transduction Stress Surface T-Lymphocyte Testing Tonsil Transcriptional Regulation Translational Research Transplantation Tumor Immunity Work base cancer cell cancer immunotherapy cancer therapy clinical application cytotoxicity experimental study graft vs leukemia effect immunoregulation improved in vivo innovation loss of function lymph nodes notch protein novel p80 natural killer cell receptor perforin peripheral blood post-transplant prevent receptor response stem cells transcription factor tumor immunology

项目摘要

PROJECT SUMMARY/ABSTRACT Our long-term goal in this project is to elucidate the mechanisms of human natural killer cell development in order to apply the processes of NK cell biology in the treatment of cancer. Natural killer (NK) cells recognize malignant cells lacking self-MHC molecules on their surface, thus targeting them for perforin-mediated cytotoxicity. NK cells comprise an important role in the innate immune response to malignancy, and indeed cancers such as acute myeloid leukemia (AML) have been shown to have impaired NK cell development and function. Therefore, understanding the yet unknown mechanisms regulating NK cell maturation in both the normal and disease settings will improve translational research efforts for cancer therapy. Our ongoing work investigates NK cell developmental pathways occurring in secondary lymphoid tissues (SLTs; including tonsils and lymph nodes). In our current studies, we observed that activation of the Notch signaling pathway results in a key transition during development from a non-functional phenotype to a functionally mature NK cell. Moreover, we detected constitutive expression of the transcriptionally-active domain of Notch in mature NK cells freshly isolated from tonsils, thus supporting the physiologic importance of Notch in regulating the functional phenotype of mature NK cells. We hypothesize that Notch signaling in the SLT microenvironment regulates the developmental transition from immature to functional NK cells. We further hypothesize that signaling through the aryl hydrocarbon receptor (AHR), which we observe is activated in AML, alters Notch signaling to inhibit NK cell development. Thus our aims are 1) to determine the mechanism by which Notch is activated in SLTs to promote NK cell functional maturation; and 2) to determine how AHR modulates Notch to antagonize NK cell maturation. To test this hypothesis, we will perform in vitro culture studies and in vivo adoptive transfer experiments using NK and other SLT-resident cells isolated from human tonsils. We will identify the direct gene targets of activated Notch in NK cells to determine how Notch regulates the transcription of critical molecules for NK cell function. Finally, we will identify how AHR modulates Notch signaling in NK cells. The overall significance of this project will address a relevant gap in knowledge regarding the regulation of human NK cell maturation in the SLT microenvironment. This project represents a novel and innovative approach to cancer immunology because it combines both mechanistic studies of an important signaling pathway, and also seeks to identify how cancers such as AML can evade the human immune system. Successful completion of these aims will improve our understanding of the normal processes of NK cell development with the goal of applying these discoveries toward novel immune-based therapies for cancer.

项目概要/摘要我们这个项目的长期目标是阐明人类自然杀伤细胞发育的机制为了将 NK 细胞生物学过程应用于癌症治疗。自然杀伤 (NK) 细胞识别恶性细胞表面缺乏自身 MHC 分子，因此可以将其作为穿孔素介导的靶标细胞毒性。 NK 细胞在针对恶性肿瘤的先天免疫反应中发挥着重要作用，事实上诸如急性髓性白血病（AML）之类的癌症已被证明会损害 NK 细胞的发育和功能。因此，了解调节 NK 细胞成熟的尚不清楚的机制正常和疾病环境将改善癌症治疗的转化研究工作。我们正在进行的工作研究次级淋巴组织（SLT；包括扁桃体）中发生的 NK 细胞发育途径和淋巴结）。在我们目前的研究中，我们观察到 Notch 信号通路的激活会导致从非功能性表型到功能性成熟 NK 细胞发育过程中的关键转变。而且，我们新鲜检测到成熟 NK 细胞中 Notch 转录活性结构域的组成型表达从扁桃体中分离出来，从而支持了 Notch 在调节功能表型方面的生理重要性成熟的 NK 细胞。我们假设 SLT 微环境中的 Notch 信号调节从未成熟的NK细胞到有功能的NK细胞的发育转变。我们进一步假设通过我们观察到芳烃受体 (AHR) 在 AML 中被激活，它会改变 Notch 信号传导以抑制 NK 细胞发展。因此，我们的目标是 1) 确定 Notch 在 SLT 中被激活的机制，以促进 NK细胞功能成熟； 2) 确定 AHR 如何调节 Notch 以拮抗 NK 细胞成熟。为了检验这一假设，我们将使用以下方法进行体外培养研究和体内过继转移实验从人类扁桃体中分离出 NK 和其他 SLT 驻留细胞。我们将确定激活的直接基因靶标在 NK 细胞中进行 Notch，以确定 Notch 如何调节 NK 细胞功能关键分子的转录。最后，我们将确定 AHR 如何调节 NK 细胞中的 Notch 信号传导。本项目的总体意义将解决 SLT 中人类 NK 细胞成熟调节方面的相关知识空白微环境。该项目代表了一种新颖且创新的癌症免疫学方法，因为它结合了重要信号通路的机制研究，并试图确定癌症如何例如AML可以逃避人体免疫系统。成功完成这些目标将改善我们的了解 NK 细胞发育的正常过程，旨在将这些发现应用于基于免疫的新型癌症疗法。