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Targeting factor B to prevent transplant rejection

靶向因子 B 预防移植排斥

基本信息

批准号：
8873752
负责人：
Peter Scott Heeger
金额：
$ 27.3万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
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：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8873752
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 public health relevance research study screening

项目摘要

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.