Integrating Mechanistic Insights from Diverse Models to Prevent CMV Reactivation following Transplantation

整合不同模型的机制见解以防止移植后 CMV 重新激活

基本信息

批准号：
8934950
负责人：
Michael M Abecassis
金额：
$ 230.59万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8934950
关键词：
Acute Animal Model Antigens Antiviral Agents Bone Marrow Cell Culture Techniques Cell Differentiation process Cell Lineage Cell Separation Chromatin Chronic Clinical Clinical Research Cytomegalovirus DNA-Directed DNA Polymerase Development Effectiveness Environment Enzymes Epigenetic Process Fostering Gene Expression Goals Graft Rejection Health Hematopoietic stem cells Histones Histopathology Human Immediate-Early Genes Immune Immune Tolerance Immune response Immunosuppression Immunosuppressive Agents In Vitro Infection Inflammation Mediators Inflammatory Inflammatory Response Kidney Transplantation Lead Life Mediating Mediator of activation protein Modeling Modification Molecular Molecular Virology Murid herpesvirus 1 Mus Myelogenous Myeloid Progenitor Cells Operative Surgical Procedures Organ Transplantation Outcome Pharmaceutical Preparations Protocols documentation Research Services Signal Pathway Signal Transduction Site Testing Therapeutic Toxic effect Transplant Recipients Transplantation Transplantation Tolerance Viral Viral Genes Viral Genome Virus base clinically relevant design gene repression genome-wide histone modification improved in vitro Model in vivo insight lytic replication novel strategies prevent programs prophylactic reactivation from latency resistant strain transcription factor viral DNA

项目摘要

DESCRIPTION (provided by applicant): Overall Reactivation of latent Cytomegalovirus (CMV) remains an important clinical problem following transplantation, despite the prophylactic use of efficacious antiviral agents. Because these target the viral DNA polymerase, they are only active after the virus has reactivated from latency. Their effectiveness is also limited by toxicities and by the emergence of resistant strains. Donor- specific allo-immune tolerance, whereby a transplant recipient is hypo-responsive to donor antigens but continues to have intact immune-responsiveness to other foreign antigens has been the `Holy Grail' of transplantation since the early 1950's. Recently, several experimental protocols have achieved this goal, and the `era of tolerance' seems near. Prior studies have demonstrated that murine CMV (MCMV) reactivation requires the combination of an allo-inflammatory response and immunosuppressive drugs (ISD), while a donor-specific tolerant model would abrogate the inflammatory response, and avoid the need for ISD. Also recently, two central themes have emerged from a combination of studies of animal models of MCMV reactivation and ex vivo/in vitro models of HCMV reactivation: expression of viral genes involved in lytic replication is repressed by epigenetic factors that induce heterochromatinization of viral genomes; and signaling pathways activated by an inflammatory immune response induce reactivation of the virus through epigenetic reprogramming of viral DNA, such that the immediate early genes are released from transcriptional repression, leading to lytic replication. These themes form the basis for studies proposed in 3 separate but inter-related projects studying: 1) Mechanisms of reactivation of latent MCMV following kidney transplantation in a clinically relevant model; 2) Mechanisms of latency and reactivation of HCMV in myeloid lineage cells; and 3) MCMV infection, latency and reactivation in transplantation tolerance. Three Cores will support services needed for the successful completion of studies within these Projects: A) Microvascular surgery and histopathology; B) Precision cell isolation and analysis; and C) Administrative services. The unifying and central hypothesis of the Program Project is that reactivation of latent CMV is induced by inflammatory mediators, which activate signaling pathways, leading to epigenetic reprogramming of viral genomes, resulting in induction of immediate early (IE) gene expression, and ultimately, to reactivation of infectious virus. We believe that blockade of these signaling pathways, either by interfering with specific signaling pathways, blocking epigenetic modifications, or by donor- specific tolerance, prevent reactivation of CMV. We anticipate that integrating mechanistic insights derived from the three projects in this highly collaborative effor will be decisive in moving the field forward and in fostering the development of novel strategies to prevent, rather than treat CMV reactivation.

描述（由申请人提供）：尽管预防性使用有效的抗病毒剂，但在移植后，潜在的巨细胞病毒（CMV）的总体重新激活仍然是一个重要的临床问题。由于这些靶向病毒DNA聚合酶，因此仅在病毒从潜伏期重新激活后才活跃。它们的有效性也受到毒性的限制，通过抗性菌株的出现。供体特定的同种免疫耐受性，因此，移植受者对供体抗原具有不反应，但自1950年代初以来，对其他外国抗原的免疫反应一直是对其他外国抗原的完整免疫反应性。最近，一些实验方案实现了这一目标，“宽容时代”似乎临近。先前的研究表明，鼠CMV（MCMV）的重新激活需要将异炎反应和免疫抑制药物（ISD）组合在一起，而供体特异性的耐受模型可以消除炎症反应，并避免对ISD的需求。同样，最近，来自MCMV重新激活的动物模型和HCMV重新激活的体外模型的动物模型的研究也出现了两个中心主题：参与裂解复制的病毒基因的表达受到诱导病毒基因组异染色体化的表观遗传因子的抑制。通过炎症免疫反应激活的信号通路通过病毒DNA的表观遗传重编程引起病毒的重新激活，从而使直接的早期基因从转录抑制中释放出来，从而导致裂解复制。这些主题构成了在3个单独但相互关联的项目研究中提出的研究的基础：1）在临床相关模型中肾脏移植后肾移植后潜在MCMV重新激活的机制； 2）髓样谱系细胞中HCMV的潜伏期和重新激活的机制； 3）MCMV感染，移植耐受性中的潜伏期和重新激活。三个核心将支持成功完成这些项目中研究所需的服务：a）微血管手术和组织病理学； b）精确细胞分离和分析； c）行政服务。该程序项目的统一和中心假设是，潜在CMV的重新激活是由炎症介质诱导的，炎症介体激活了信号通路，从而导致病毒基因组的表观遗传重编程，从而导致早期（IE）基因表达和最终的早期（IE）基因表达，最终导致感染性病毒的重新激活。我们认为，通过干扰特定的信号通路，阻断表观遗传修饰或通过供体公差来阻止这些信号通路的阻塞，以防止CMV重新激活。我们预计，在这个高度协作的效果中，从三个项目中得出的机械洞察力集成在推动该领域向前发展和促进新型策略以预防而不是治疗CMV重新激活的发展方面具有决定性的作用。