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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：
9099718
负责人：
Michael M Abecassis
金额：
$ 230.82万
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/9099718
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 Cytomegalovirus Infections 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 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 outcome 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）：尽管预防性使用了有效的抗病毒药物，但移植后潜伏巨细胞病毒（CMV）的全面再激活仍然是一个重要的临床问题。因为这些靶向病毒DNA聚合酶，它们只有在病毒从潜伏期重新激活后才有活性。它们的效力也受到毒性和