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:
- 金额:$ 37.2万
- 依托单位:
- 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:
- 关键词:AcuteAcute Graft Versus Host DiseaseAllogeneic Bone Marrow TransplantationAllogenicAutoimmunityB-Cell ActivationB-Cell DevelopmentB-LymphocytesBenignBiological PreservationBone Marrow TransplantationCellsChronicClinicalComplicationDevelopmentDiseaseFunctional disorderGenerationsGeneticGoalsHematopoieticHomeostasisHumanImmune responseIndividualInfectionInterferon Type IIInterferonsKnock-outKnockout MiceMalignant - descriptorMalignant NeoplasmsMemoryMicroRNAsModelingMolecularMorbidity - disease rateMusOligonucleotidesOrganPathogenicityPeptide Nucleic AcidsPharmacologyPlayProductionProphylactic treatmentRegulatory T-LymphocyteResearchRoleSeverity of illnessT cell responseT-LymphocyteTestingTherapeuticTherapeutic procedureTimeTranslatingTransplantationUntranslated RNAXenograft procedurechronic graft versus host diseaseclinical applicationclinically relevantdisabilitydriving forcegraft vs host diseasehematopoietic cell transplantationin vivoinhibitor/antagonistleukemialocked nucleic acidmigrationmortalitymouse modelpre-clinicalpreclinical studypreventpublic health relevanceresponsetargeted treatmenttherapeutic targettumor
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.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Xue-Zhong Yu其他文献
Xue-Zhong Yu的其他文献
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{{ truncateString('Xue-Zhong Yu', 18)}}的其他基金
Targeting PIM-2 Kinase for Improving Cancer Immunotherapy
靶向 PIM-2 激酶以改善癌症免疫治疗
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10364948 - 财政年份:2022
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Targeting PIM-2 Kinase for Improving Cancer Immunotherapy
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ER stress pathways regulate T-cell allogeneic and anti-tumor responses
ER应激通路调节T细胞同种异体和抗肿瘤反应
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10430505 - 财政年份:2022
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$ 37.2万 - 项目类别:
Control of GVHD by Probiotics with individual Commensal Bacteria
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10434993 - 财政年份:2022
- 资助金额:
$ 37.2万 - 项目类别:
ER stress pathways regulate T-cell allogeneic and anti-tumor responses
ER应激通路调节T细胞同种异体和抗肿瘤反应
- 批准号:
10577856 - 财政年份:2022
- 资助金额:
$ 37.2万 - 项目类别:
Control of GVHD by Probiotics with individual Commensal Bacteria
益生菌与单个共生细菌控制 GVHD
- 批准号:
10617324 - 财政年份:2022
- 资助金额:
$ 37.2万 - 项目类别:
Targeting IRE-1a/XBP-1 Axis for Control of Chronic GVHD and Leukemia Relapse
靶向 IRE-1a/XBP-1 轴控制慢性 GVHD 和白血病复发
- 批准号:
10578550 - 财政年份:2018
- 资助金额:
$ 37.2万 - 项目类别:
Targeting IRE-1a/XBP-1 Axis for Control of Chronic GVHD and Leukemia Relapse
靶向 IRE-1a/XBP-1 轴控制慢性 GVHD 和白血病复发
- 批准号:
10179448 - 财政年份:2018
- 资助金额:
$ 37.2万 - 项目类别:
Separation of GVH and GVL Responses Using Alloreactive CD8 iTregs
使用同种异体反应性 CD8 iTreg 分离 GVH 和 GVL 反应
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9333524 - 财政年份:2017
- 资助金额:
$ 37.2万 - 项目类别:
Control of GVHD and Leukemia Relapse by Targeting Cell Metabolism
通过靶向细胞代谢控制 GVHD 和白血病复发
- 批准号:
8815578 - 财政年份:2015
- 资助金额:
$ 37.2万 - 项目类别:
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