Targeting factor B to prevent transplant rejection

靶向因子 B 预防移植排斥

• 批准号: 9000104
• 负责人: Peter Scott Heeger
• 金额: $ 20.69万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000104
• 关键词: Age related macular degeneration; Allografting; Animal Model; Animals; Bacteriophages; Binding; Biological Assay; Biological Models; Biopsy; Cardiac; Cardiac Surgery procedures; Complement; Complement Activation; Complement Factor B; Data; Functional disorder; Gene Expression; Genes; Goals; Graft Rejection; Graft Survival; Grant; Health; Heart; Heart Transplantation; Hemolytic-Uremic Syndrome; Human; Immune response; In Vitro; Inflammation; Inflammatory Response; Injury; Ischemia; Kidney Diseases; Kinetics; Lectin; Mediator of activation protein; Modeling; Mus; Myocardial; Myocardial Ischemia; Myocardium; Operative Surgical Procedures; Organ; Organ Donor; Organ Survival; Organ Transplantation; Outcome; Pathway interactions; Patients; Peptide Library; Peptide Phage Display Library; Peptides; Plasma; Play; Process; Publishing; Reperfusion Therapy; Resistance; Role; Specificity; Testing; Tissues; Transplantation; Troponin I; Work; attenuation; blocking factor; clinical practice; clinically relevant; design; effective therapy; efficacy testing; experience; human tissue; improved; in vivo; inhibitor/antagonist; insight; mouse model; novel; pre-clinical; prevent; research study; screening

 DESCRIPTION (provided by applicant): Ischemia followed by reperfusion (IR), which occurs unavoidably during organ transplantation, elicits immune responses that contribute to graft dysfunction. Delineating novel, effective therapies to prevent IR injury has the potential to change clinical practice and improve patient health following organ transplantation. The goals of this project are to define the role of complement factor B (fB) in post-transplant injury, identify new mouse and human fB antagonists and begin to test them in animal models. The long term goal is to use the inhibitors to prevent allograft injury in humans. Our combined published and preliminary data demonstrate that: blocking complement activation in a donor organ prolongs allograft survival in mice; fB gene expression is increased in biopsies of heart transplantation patients compared with levels in normal heart tissue, and correlates with graft rejection grades; in a murine myocardial IR model, injury is significantly reduced in fB-/- mice; fB is significantly activated in the hearts of patients undergoing open heart surgery, i.e., experiencing surgically-induced global heart ischemia; in these patients, the levels of Bb, the activated fB fragment, correlate with the post- surgical increase of circulating cardiac troponin I, a marker of myocardia injury. Thus, fB expression and activation in donor organs are important in graft rejection. The specific aims are: 1) To identify small peptide antagonists specific for murine and for human fB using a phage display peptide library. 2) To determine the role of fB in transplant rejection in mice and to test the efficacy of fB inhibition. We expect that the studies will identify novel fB inhibitors, provide new insight into mechanisms of IR injury and transplant rejection, and provide preclinical data to support human studies to block fB in vivo.

 描述（由适用提供）：缺血，然后再灌注（IR），在器官移植期间不可避免地发生，引发了导致晶粒功能障碍的免疫反应。描述新的，有效的预防IR损伤的疗法有可能改变临床实践并改善器官移植后患者健康。该项目的目标是确定补体因子B（FB）在移植后伤害中的作用，确定 新的小鼠和人类FB拮抗剂，并开始在动物模型中测试它们。长期目标是使用抑制剂来防止人类同种异体移植损伤。我们合并的已发表和初步数据表明：阻断供体器官中的完成激活延长了小鼠的同种异体移植生存；与正常心脏组织的水平相比，心脏移植患者活检的FB基因表达增加，并且与移植排斥级别相关。在鼠心肌IR模型中，FB - / - 小鼠的损伤显着降低。 FB是显着的 在接受开放心脏手术的患者的心脏中激活，即患有外科手术引起的全球心脏缺血；在这些患者中，BB的水平，激活的FB片段与循环心脏肌钙蛋白I（心肌损伤的标志物）的术后增加相关。那就是供体器官中的FB表达和激活在移植排斥中很重要。具体目的是：1）使用噬菌体显示肽库鉴定针对鼠和人FB的小胡椒拮抗剂。 2）确定FB在小鼠移植排斥中的作用并测试FB抑制剂的有效性。我们预计这些研究将确定新颖的FB抑制剂，为IR损伤和移植排斥的机制提供新的见解，并提供临床前数据以支持人类研究以阻止体内FB。