MicroRNA Regulates Graft-versus-Host Disease

MicroRNA 调节移植物抗宿主病

• 批准号: 9206138
• 负责人: Xue-Zhong Yu
• 金额: $ 37.2万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206138
• 关键词: Acute; Acute Graft Versus Host Disease; Allogeneic Bone Marrow Transplantation; Allogenic; Autoimmunity; B-Cell Activation; B-Cell Development; B-Lymphocytes; Benign; Biological Preservation; Bone Marrow Transplantation; Cells; Chronic; Clinical; Complication; Development; Disease; Functional disorder; Generations; Genetic; Goals; Hematopoietic; Homeostasis; Human; Immune response; Individual; Infection; Interferon Type II; Interferons; Knock-out; Knockout Mice; Malignant - descriptor; Malignant Neoplasms; Memory; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Oligonucleotides; Organ; Pathogenicity; Peptide Nucleic Acids; Pharmacology; Play; Production; Prophylactic treatment; Regulatory T-Lymphocyte; Research; Role; Severity of illness; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic procedure; Time; Translating; Transplantation; Untranslated RNA; Xenograft procedure; chronic graft versus host disease; clinical application; clinically relevant; disability; driving force; graft vs host disease; hematopoietic cell transplantation; in vivo; inhibitor/antagonist; leukemia; locked nucleic acid; migration; mortality; mouse model; pre-clinical; preclinical study; prevent; public health relevance; response; targeted treatment; therapeutic target; tumor

 DESCRIPTION (provided by applicant): Hematopoietic cell transplantation (HCT) can cure a variety of benign and malignant hematopoietic disorders, but acute and chronic graft-versus-host disease (GVHD) remains the primary case of transplant-related morbidity, disability and mortality, thereby limiting the use of HCT. Although progress in understanding the pathophysiology of GVHD has been continually made, there are significant gaps in understanding molecular mechanisms that regulate the pathogenicity of allogeneic T and B cells in GVHD. Recent evidence demonstrates that microRNAs (miRs), a class of small noncoding RNAs, play a significant role in orchestrating immune responses. miR-17-92 cluster encodes 6 miRs and plays an important role in a variety of immune responses including anti-infection, anti-tumor and autoimmunity. However, the role of this cluster in the modulation of T- and B-cell responses in GVHD and graft-versus-leukemia (GVL) has not been explored. Our long-term goal is to prevent and treat GVHD while preserving the GVL effect after HCT by targeting miR-17-92 cluster in humans. The objective of this proposal is to achieve this goal in pre-clinical bone marrow transplantation (BMT) models in mice. The central hypothesis is that miR-17-92 controls T- and B-cell activation and function in alloresponse, and thus blockade of this cluster will significantly alleviate acute and chronic GVHD while preserving GVL activity. This hypothesis is strongly supported by our preliminary studies, where we found that miR-17-92-deficient T cells had significantly reduced ability to cause acute GVHD while retaining GVL activity in murine models of allogeneic BMT. Furthermore, synthetic anti-miR-17 or anti-miR-19 locked nucleic acid (LNA) antagomirs also significantly reduced donor T-cell expansion, IFN production, and GVHD severity. In current proposal, we will test our hypothesis and accomplish the objectives by pursuing 3 Specific Aims: 1) To define the role of miR-17-92 in T-cell response in aGVHD and GVL effect; 2) To determine the role of miR-17-92 in T-cell and B-cell response in cGVHD; 3) To evaluate the effects of blocking miR-17-92 in GVHD and GVL activity. The proposed studies are expected to enhance our understanding in the roles of miR-17-92 in regulating T- and B-cell responses, and to validate miR-17-92 as therapeutic targets for the control of GVHD while preserving GVL activity.

 描述（由应用提供）：造血细胞移植（HCT）可以治愈各种良性和恶性造血性疾病，但急性和慢性移植物抗宿主疾病（GVHD）仍然是与移植相关的发病率，残疾和死亡的主要案例，从而限制了HCT的使用。尽管了解GVHD的病理生理学方面的进展一直是不断做出的，但在理解分子机制方面有很大的差距，这些机制调节了GVHD中同种异体T和B细胞的致病性。最近的证据表明，MicroRNA（MIRS）是一类小型非编码RNA，在编排免疫调查中起着重要作用。 miR-17-92簇编码6个miR，并在包括抗感染，抗肿瘤和自身免疫的各种免疫调查中起重要作用。但是，尚未探索该群集在GVHD和GRAFT-VERSUS-LEUKEMIA（GVL）中T-和B细胞响应调节中的作用。我们的长期目标是通过靶向人类中的miR-17-92簇来预防和治疗GVHD，同时保留HCT后的GVL效应。该建议的目的是在小鼠的临床前骨髓移植（BMT）模型中实现这一目标。中心假设是，miR-17-92控制着同种答管中的T和B细胞的激活和功能，因此该簇的阻断将显着减轻急性和慢性GVHD，同时保留GVL活性。我们的初步研究强烈支持了这一假设，我们发现miR-17-92缺乏T细胞具有显着降低引起急性GVHD的能力，同时在同种异体BMT的鼠模型中保留GVL活性。此外，合成抗MIR-17或抗MIR-19锁定的核酸（LNA）Antagomirs也显着降低了供体T细胞的扩张，IFN产生和GVHD的严重性。在当前的提案中，我们将通过追求3个具体目标来检验我们的假设并实现目标：1）定义miR-17-92在T细胞响应中的作用在AGVHD和GVL效应中； 2）确定miR-17-92在T细胞和B细胞反应中的作用； 3）评估阻断miR-17-92在GVHD和GVL活性中的影响。预计拟议的研究将增强我们对miR-17-92在调节T和B细胞反应中的作用的理解，并验证miR-17-92作为控制GVHD的治疗靶标，同时保留GVL活性。