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Modulating endothelial cell immunometabolism and mitochondrial morphologyimplications for organ transplantation

调节内皮细胞免疫代谢和线粒体形态对器官移植的影响

基本信息

批准号：
10634543
负责人：
SATISH N NADIG
金额：
$ 39.79万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10634543
关键词：
Acute Affect Alloantigen Allograft Tolerance Allografting Antigen Presentation Antigen-Presenting Cells Antiinflammatory Effect Blood Vessels Brain Death Cell Communication Cell Line Cells Cessation of life Chronic Cryopreservation Data Dose Endothelial Cells Endothelium Environment Event Functional disorder Goals Graft Rejection Graft Survival Heart Transplantation Heterogeneity Imaging Techniques Immune Immunity Immunologics Immunosuppression In Vitro Infection Infiltration Inflammatory Injury Ischemia Laboratories Link Longevity Mainstreaming Maintenance Malignant Neoplasms Mediating Metabolic Metabolism Mitochondria Modeling Morphology Mus Organ Organ Preservation Organ Procurements Organ Transplantation Organ failure Pathology Patients Peptides Pharmaceutical Preparations Phase Phenotype Play Process Regimen Reperfusion Injury Reperfusion Therapy Role Severities Shapes Solid Stress T memory cell T-Cell Activation T-Lymphocyte Therapeutic Therapeutic immunosuppression Time Transplantation Tubular formation Vascular Diseases Vertebral column allograft rejection clinical translation clinically relevant curative treatments cytokine effector T cell end-stage organ failure experimental study functional outcomes graft dysfunction graft failure immune function immunogenic immunogenicity immunological synapse implantation improved improved outcome in vivo in vivo Model inhibitor ischemic injury metabolic profile natural hypothermia novel novel strategies novel therapeutic intervention post-transplant preconditioning preservation programs promoter response side effect small molecule standard of care stressor synaptic function transplant model

项目摘要

ABSTRACT: Organ transplantation is a mainstream therapy for patients with organ failure; however, despite major advances in the field, there has been little progress regarding two major components of transplantation -- organ preservation and maintenance immunosuppression. Although essential, immunosuppressive therapy carries a significant side-effect burden, often leading to patient death and graft failure. In addition, the process of organ procurement most often includes use of grafts from brain dead donors followed by hypothermic preservation of the organs in storage solutions. During these events, the endothelial cells (EC) in the organ allografts are primed immunologically and are then subjected to the insults of reperfusion. This early injury predisposes the EC to inappropriate antigen presentation and effects of chronic graft dysfunction, including graft vasculopathy leading to long-term graft failure. Hypothermic preservation changes the metabolism of the allograft, which in turn is hypothesized to alter the immunogenicity of the ECs ultimately affecting cellular functional outcomes. Central to this cascade is the role of the mitochondria in shaping the immunometabolic milieu of the allograft in the face of cold ischemia and reperfusion injury. In this proposal we, for the first time, explore the mechanistic relationship between the mitochondrial morphology and immunometabolism of ECs and their immunogenicity in the setting of transplantation. We build upon our own data to assess the effects of forcing mitochondrial ultrastructural changes on the immunogenic profile of EC during the preservation phase of transplantation. We propose that by dampening the early immunogenic effects of ECs, we can create the opportunity to induce allograft tolerance with the use of reduced immunosuppressive regimens thereby reducing the deleterious consequences of these necessary drugs. We will employ the scientific premise of reprograming ECs to a more tolerogenic state by altering their metabolic core such that their ability to induce proinflammatory changes from alloreactive T cells are diminished. Using clinically relevant in vivo models of transplantation, we anticipate that altering EC mitochondria will improve graft survival and abrogate the pathology associated with allograft rejection. Using our preliminary data as a backbone we hypothesize that cold ischemia exacerbates the immunogenic capacity and metabolic profile of EC by altering mitochondrial morphology resulting in allograft injury. Additionally, with the following aims, our goal will be to protect organ allografts and skew the EC to a more tolerogenic phenotype. Aim 1. We will determine the impact of mitochondrial morphology during organ preservation on the immunogenicity of endothelial cells in vitro. Aim 2. We aim to assess the impact of mitochondrial morphology on ischemia reperfusion injury and acute transplant rejection in vivo. Pre-treatment with mitochondrial fusion therapeutics will shift the current standard of care in transplantation.

摘要：器官移植是器官衰竭患者的主流治疗方法；然而,尽管