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FAS Controls Exosome-Mediated miRNA Transfer in MSC-Based Therapy

FAS 在基于 MSC 的治疗中控制外泌体介导的 miRNA 转移

基本信息

批准号：
9348626
负责人：
Chi-Der Chen
金额：
$ 7.08万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-07 至 2019-04-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9348626
关键词：
Adenoviruses Autoimmune Diseases Autoimmune Responses Award Biological Assay Blood Vessels Bone Marrow Bone Resorption Cell Differentiation process Cell Lineage Cell Therapy Cells Cellular Structures Chronic Clinical Collagen Communication Complex Connective Tissue Diseases Data Deposition Development Disease Disease Management Exocytosis FRAP1 gene Fracture Functional disorder Goals Head and neck structure High Prevalence Homeostasis Human Immune Immunoprecipitation Impairment In Vitro Infiltration Infusion procedures Interleukin 4 Receptor Knockout Mice Knowledge Label Mandible Mediating Membrane Membrane Protein Traffic Mentorship Mesenchymal Stem Cell Transplantation Mesenchymal Stem Cells MicroRNAs Mus Organ Osteogenesis Osteopenia Osteoporosis Osteoporotic Outcome Pathogenesis Pathogenicity Patients Phase Phenotype Play Production Property Regulation Research Research Personnel Role Scleroderma Sclerosis Signal Transduction Skin Small Interfering RNA Stem cells Supervision Systemic Scleroderma Th2 Cells Therapeutic Therapeutic Effect Tissues Training Transplantation United States National Institutes of Health Vascular Diseases Vertebral Bone Vesicle bone loss career chemokine clinical application collaborative environment craniofacial cytokine disease phenotype epigenetic regulation exosome gene therapy human disease immunoregulation improved in vivo inhibitor/antagonist knock-down lipid biosynthesis microscopic imaging migration neutrophil novel novel therapeutics overexpression public health relevance skills skin disorder stem cell therapy trafficking translational study tsk mouse

项目摘要

Project Description Systemic sclerosis/scleroderma (SSc) is a connective tissue disease characterized by vascular, immune and fibrotic changes in the skin and internal organs. SSc patients are known to have high prevalence of osteopenia, but the pathophysiological mechanism causing this osteoporosis in SSc patients is unknown. Systemic infusion of mesenchymal stem cells (MSCs) yields a therapeutic effect in a variety of autoimmune diseases; however, the reasons behind this MSC-based therapy are not fully understood. As a secretome, MSCs release large amounts of cytokines and small vesicles for immunoregulation and communication with surrounding cells. The goal of this proposal is to investigate how small vesicles are controlled by a set of membrane traffic proteins for cell component reuse in MSC transplantation (MSCT). My preliminary data show that MSCT significantly rescues disease phenotypes in SSc mice through rebuilding tissue homeostasis and lineage commitment of host MSCs. miRNA-151-5p is reused by recipient MSCs through exosome trafficking resulting in markedly recovered lineage selection of host MSCs. A micro-vesicle trafficking complex assembled in donor MSCs regulated exocytosis for exosome-mediated miRNA transfer. In addition, developmental endothelial locus-1 (Del-1), an immune suppressive molecule, expresses in MSCs and releases via exosomes to inhibit neutrophil migration. The central hypothesis of this proposal is that cell component transferred from donor to recipient MSCs ameliorates autoimmune disease phenotypes through FAS-assembled exocytotic machinery. During the K99 phase, I will explore the efficacy of MSCT in SSc mice and uncover the interplay between immune cells and tissue-specific stem cells to elucidate the pathophysiological mechanism of SSc (Aim 1; K99). Since miRNA-151-5p has been identified to transfer from donor to recipient MSCs, I will determine the function of miRNA-151-5p in MSC differentiation and use miRNA-151-5p gene therapy in SSc mice (Aim 2; K99). During the R00 phase, I will determine the role of the exosome in MSCT by direct infusion of exosomes for disease treatment and examine the role of the exocytosis molecule Rab27a in regulation of exosome release. I will identify a novel micro-vesicle trafficking complex from MSCs and determine its function in controlling cell component reuse (Aim 3; R00). Finally, I will examine the therapeutic effect of Del-1, which can be released via exosomes from donor MSCs to restrain cytokine production and disease phenotypes (Aim 4; R00). Upon successful completion of the Specific Aims, this translational study will extend our knowledge of SSc pathogenesis and describe detailed mechanisms of MSC-based therapy. Under my primary mentorship of Drs. Hajishengallis and Shi, the training plan will provide the opportunity to extend and develop the necessary knowledge and skills within a collaborative environment. An identified outstanding mentorship team and collaborators will broaden my training in different research fields. Under their supervision and guidance, this NIH K99/R00 Award will largely improve my ability to begin my scientific career as an independent investigator.

项目描述系统性硬化症/硬皮病（SSc）是一种结缔组织疾病，其特征在于血管性、免疫性和皮肤和内部器官的纤维化变化。已知SSc患者骨质减少的患病率高，但引起SSc患者骨质疏松的病理生理机制尚不清楚。全身输注间充质干细胞（MSC）在多种自身免疫性疾病中产生治疗效果;然而，这种基于MSC的治疗背后的原因还没有完全理解。作为一种分泌体，MSC释放大量的大量的细胞因子和用于免疫调节和与周围细胞通讯的小囊泡。的这项计划的目的是研究小泡是如何被一组膜运输蛋白控制的， MSC移植（MSCT）中的细胞成分再利用。我的初步数据显示，通过重建组织稳态和谱系定型，宿主MSC。miRNA-151- 5 p通过外泌体运输被受体MSC再利用，导致显著的细胞凋亡。恢复宿主MSC的谱系选择。在供体骨髓间充质干细胞中组装的微囊泡运输复合物调节外泌体介导的miRNA转移的胞吐作用。此外，发育内皮基因座-1 （Del-1）是一种免疫抑制分子，在MSC中表达并通过外泌体释放以抑制中性粒细胞迁移这一建议的中心假设是，从供体转移到供体的细胞成分，受体间充质干细胞通过FAS组装的胞吐作用改善自身免疫性疾病表型机械.在K99阶段，我将探索MSCT在SSc小鼠中的疗效，并揭示其相互作用。免疫细胞和组织特异性干细胞之间的关系，以阐明SSc的病理生理机制 (Aim 1; K99）。由于miRNA-151- 5 p已被鉴定为从供体转移到受体MSC，我将确定miRNA-151- 5 p在MSC分化中的功能，并在SSc中使用miRNA-151- 5 p基因治疗小鼠（Aim 2; K99）。在R 00阶段，我将通过直接输注确定外泌体在MSCT中的作用外泌体用于疾病治疗，并检查胞吐分子Rab 27 a在调节外泌体释放我将从骨髓间充质干细胞中鉴定一种新型的微囊泡运输复合物并确定其功能在控制单元组件重用方面（目标3; R 00）。最后，我将检查Del-1的治疗效果，可以通过外来体从供体MSC释放，以抑制细胞因子的产生和疾病表型（Aim 4; R00）。在成功完成具体目标后，这项翻译研究将扩展我们的知识， SSc的发病机制，并描述了基于MSC的治疗的详细机制。在我的主要指导下， Drs. Hajishengallis和施，培训计划将提供机会，以扩大和发展必要的在协作环境中的知识和技能。一个确定的优秀辅导团队，合作者将扩大我在不同研究领域的培训。在他们的监督和指导下， NIH K99/R 00奖将在很大程度上提高我作为独立研究者开始科学生涯的能力。