Manipulation of MHC expression using TGF-beta2 to reduce mesenchymal stem cell immunogenicity

项目摘要/摘要 拟议的导师研究科学家发展奖(K01)将为候选人Alix博士提供 Berglund，DVM，博士，拥有必要的知识、培训和经验，可以成为一名独立的 免疫学和间充质干细胞(MSC)生物学领域的转译生物医学研究员。 间充质干细胞是治疗炎症性和免疫介导性疾病的一种很有前途的细胞来源。同种异体疗法 将提供经济有效的治疗，但目前受到受者免疫排斥的阻碍 表达错配主要组织相容性复合体(MHC)分子的供体MSCs。MSCs是非常强大的 然而，免疫调节和对MHC表达的操纵可能足以使供体MSCs 逃避接受者的免疫反应。这一提议的核心假设得到了斯特朗的支持 初步研究表明，转化生长因子-β-2(转化生长因子-β-2)可下调间充质干细胞MHC-I的表达 和MHC II基因转录，从而降低MHC不相合MSCs的体内免疫原性。这个 该项目的目的是1)确定转化生长因子-β-2如何下调间充质干细胞中间质细胞间充质干细胞的表达和2)确定 转化生长因子-β-2治疗对体内骨髓间充质干细胞免疫原性的影响小鼠和马的MSCs将被用来 阐明转化生长因子-β-2信号通路增加对人类的翻译潜能(目标1)和非炎症性 炎症小鼠模型将被用来分析免疫系统对转化生长因子-β2治疗的反应 骨髓间充质干细胞体内培养(AIM 2)。完成拟议的研究是朝着提高疗效和 同种异体间充质干细胞临床应用的安全性。为了实现这些目标，伯格伦德博士将以她的背景为基础 在间充质干细胞生物学、免疫学和大型动物模型中发展分子方面的专业知识 免疫学技术、体内同种异体免疫反应分析和小鼠模型的应用。Dr。 Berglund的指导团队结合了免疫学、间充质干细胞和遗传学的专业知识， 帮助她转变为一名独立的翻译生物医学研究人员。这项工作将会完成 主要在北卡罗来纳州立大学兽医学院，该学院非常有资格 培训临床转化型科学家，并在北卡罗来纳大学教堂山分校开展额外工作。

PROJECT SUMMARY/ABSTRACT The proposed Mentored Research Scientist Development Award (K01) will provide the candidate, Dr. Alix Berglund, DVM, PhD, with the necessary knowledge, training, and experience to become an independent translational biomedical researcher in the fields of immunology and mesenchymal stem cell (MSC) biology. MSCs are a promising cell source for treating inflammatory and immune-mediated diseases. Allogeneic therapy would provide cost-effective and efficient treatment, but is currently hindered by recipient immune rejection of donor MSCs expressing mismatched-major histocompatibility complex (MHC) molecules. MSCs are strongly immunomodulatory, however, and manipulation of MHC expression may be sufficient to allow donor MSCs to evade recipient immune responses. The central hypothesis of this proposal, which is supported by strong preliminary research, is that treating MSCs with transforming growth factor-β2 (TGF-β2) downregulates MHC I and MHC II gene transcription thereby reducing the in vivo immunogenicity of MHC-mismatched MSCs. The aims of this project are to 1) Identify how TGF-β2 downregulates MHC expression in MSCs and 2) Determine how TGF-β2 treatment affects MSC immunogenicity in vivo. Both murine and equine MSCs will be utilized to elucidate TGF-β2 signaling pathways to increase translational potential to humans (Aim 1) and non-inflammatory and inflammatory murine models will be used to analyze how the immune system responds to TGF-β2-treated MSCs in vivo (Aim 2). Completion of the proposed research is a first step towards improving the efficacy and safety of allogeneic MSCs for clinical use. To accomplish these aims, Dr. Berglund will build on her background in mesenchymal stem cell biology, immunology, and large animal models by developing expertise in molecular immunology techniques, in vivo alloimmune response analysis, and the utilization of murine models. Dr. Berglund's mentoring team has combined expertise in immunology, mesenchymal stem cells, and genetics to facilitate her transition to an independent translational biomedical researcher. This work will be completed primarily at the North Carolina State University College of Veterinary Medicine, which is eminently qualified to train translational clinician scientists, with additional work at the University of North Carolina-Chapel Hill.