MicroRNA Regulates Graft-versus-Host Disease

MicroRNA 调节移植物抗宿主病

基本信息

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
项目类别：
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

项目摘要

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（申请人提供）：造血细胞移植（HCT）可以治愈多种良性和恶性造血疾病，但急性和慢性移植物抗宿主病（GVHD）仍然是移植相关发病、残疾和死亡的主要原因，从而限制了 HCT 的使用，尽管在了解 GVHD 的病理生理学方面不断取得进展，但在了解调节 GVHD 致病性的分子机制方面仍存在显着差距。最近的证据表明，microRNA（miR）是一类小非编码 RNA，在协调免疫反应中发挥着重要作用，miR-17-92 簇编码 6 个 miR，并在多种中发挥重要作用。然而，该簇在 GVHD 和 B 细胞反应调节中的作用。我们的长期目标是通过靶向人类的 miR-17-92 簇来预防和治疗 GVHD，同时保留 HCT 后的 GVL 效果。在小鼠临床前骨髓移植 (BMT) 模型中实现这一目标的核心假设是 miR-17-92 在同种异体反应中控制 T 细胞和 B 细胞的激活和功能，从而阻断。该簇的使用将显着减轻急性和慢性 GVHD，同时保留 GVL 活性。我们的初步研究有力地支持了这一假设，我们发现 miR-17-92 缺陷的 T 细胞在保留 GVL 活性的同时，引起急性 GVHD 的能力显着降低。此外，在同种异体 BMT 的小鼠模型中，合成的抗 miR-17 或抗 miR-19 锁定核酸 (LNA) antagomir 也显着减少了供体 T 细胞的扩增，在当前的提案中，我们将测试我们的假设并通过追求 3 个具体目标来实现目标： 1) 确定 miR-17-92 在 aGVHD 和 GVL 效应中 T 细胞反应中的作用； 2) 确定 miR-17-92 在 cGVHD 中 T 细胞和 B 细胞反应中的作用； 3) 评估阻断 miR-17-92 在 cGVHD 中的作用； GVHD 和 GVL 活性预计将增强我们对 miR-17-92 在调节 T 细胞和 B 细胞反应中的作用的理解，并验证 miR-17-92 作为控制 GVHD 的治疗靶点。保留 GVL 活性。