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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.