Gene regulatory architecture of CD56 bright natural killer cells

CD56 明亮自然杀伤细胞的基因调控结构

基本信息

批准号：
10377919
负责人：
Patrick Leonard Collins
金额：
$ 19.69万
依托单位：
OHIO STATE UNIVERSITY
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：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377919
关键词：
Activities of Daily Living Acute Myelocytic Leukemia Adopted Adoptive Cell Transfers Antibodies Architecture Automobile Driving Biological Assay Biological Models Blood Bone Marrow Cell Differentiation process Cell Therapy Cell physiology Cells Chronic Clinical Computational algorithm Cytokine Receptors Data Data Set Development Enhancers Environment Epigenetic Process Epithelial Epitope Mapping Exploratory/Developmental Grant Generations Genetic Transcription Genomics Goals Hematologic Neoplasms Heterogeneity Human Immune Immune response Immunity In Vitro Infection Infection Control Inflammation Inflammation Mediators Inflammatory Interferon Type II Invaded Label Logic Lymph Lymphocyte Lymphoid Cell Malignant Neoplasms Measurement Mediating Mediator of activation protein Molecular Mucous Membrane Mus NCAM1 gene NK cell therapy Natural Killer Cells Nature Neoplasm Metastasis Output Pathology Pathway interactions Phenotype Population Population Heterogeneity Process Production Regulator Genes Research Research Personnel Residencies Resources Sentinel Signal Transduction Solid Neoplasm Stimulus Testing Therapeutic Tissues Tonsil Transforming Growth Factor beta Xenograft procedure anti-cancer cancer immunotherapeutics cytokine cytokine therapy cytotoxic cytotoxicity design epigenome experimental study graft vs host disease immunoreaction inflammatory milieu interest intraepithelial killer factor lymph nodes multidimensional data novel prevent receptor self-renewal tissue repair tumor

项目摘要

PROJECT SUMMARY This project focuses on how genomic regulators direct natural killer (NK) cells to control infections and malignancies. In this regard, the specific aims are: 1) to determine mechanisms by which circulating and tissue- resident “helper” like NK cells epigenetically remodel into each other; and, 2) identify regulatory transition points that “lock” circulating NK cells into their cytolytic lineage, blocking the helper identities. Natural killer cells are innate lymphocytes, which means they can recognize, and normally eliminate, infections and tumors before a full immune response needs to be generated. This innate functionality makes them particularly exploitable for a new generation of therapies: NK cells cannot participate in graft-versus-host disease (important for cellular therapy), they can be armed with antibodies (required for antibody-mediated therapies), and rapidly respond to their environment (important for cytokine therapies). Given their promise in novel anti- cancer and immune therapeutics, a deeper understanding of clinically beneficial NK cell phenotypes is of high priority. Unfortunately, chronic inflammation may prevent NK cells from functioning when exploited for therapies. As such, the goal of this proposal is to define how inflammatory environments establish NK cell identities, via epigenetic programming. First, We will investigate how chronic inflammation alters the NK cell epigenome, shutting down the beneficial features of NK cells used in therapy. We will then assay NK cell heterogeneity during inflammation, including their epigenetic landscape. The output will be made available as publicly available datasets, ideally used by many researchers to identify mechanisms governing killer NK cell identities. Indeed, as this process may be dysfunctional in diverse pathologies, the data could be of interest to a wide range of fields. Many infections, solid tumors and hematological malignancies, such as acute myeloid leukemia, create environments that reprogram NK cells. Thus, the identified pathways may be a major barrier to effective immunity.

项目摘要该项目侧重于基因组调节剂如何将自然杀手（NK）细胞指导以控制感染和恶性肿瘤。在这方面，具体目的是：1）确定循环和组织的机制居民像NK细胞一样“助手”在表观上重塑彼此； 2）确定监管过渡点那个“锁定”将NK细胞循环到其细胞溶解谱系中，阻断了助手身份。天然杀伤细胞是先天淋巴细胞，这意味着它们可以识别并通常消除感染需要产生完全免疫响应之前的肿瘤。这种先天的功能使他们特别可利用新一代疗法：NK细胞不能参与移植物抗宿主病（对于细胞疗法很重要），它们可以配备抗体（抗体介导的疗法所必需的），并迅速响应其环境（对细胞因子疗法很重要）。鉴于他们在新颖的反 - 癌症和免疫治疗，对临床上有益的NK细胞表型的更深入了解很高优先事项。不幸的是，慢性炎症可能会阻止NK细胞用于治疗时的功能。像这样，该提案的目的是通过表观遗传来定义炎症环境如何建立NK细胞身份编程。首先，我们将研究慢性感染如何改变NK细胞表观基因组，关闭用于治疗的NK细胞的有益特征。然后，我们将在炎症期间断言NK细胞异质性，包括他们的表观遗传景观。该输出将作为公开可用数据集提供，理想情况下许多研究人员用来识别有关杀手NK细胞身份的机制。确实，作为这个过程在潜水员病理学中可能是功能失调的，数据可能引起了广泛的领域。许多感染，实体瘤和血液系统恶性肿瘤，例如急性髓样白血病，创造环境该重编程的NK细胞。这是确定的途径可能是有效免疫力的主要障碍。