Identification of human PECAM-1 receptor

人PECAM-1受体的鉴定

基本信息

批准号：
8352827
负责人：
Thomas David Manes
金额：
$ 8.3万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8352827
关键词：
Adult Affect Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Antigen-Presenting Cells Antigens Apical Atherosclerosis Autoimmune Diseases Blood Vessels Blood flow CD31 Antigens CD4 Positive T Lymphocytes CD8B1 gene CX3CL1 gene CXCL10 gene Cells Chimeric Proteins Chronic Development Endothelial Cells Event Extracellular Domain Fractalkine Goals Graft Rejection Hematopoietic Hour Human Human Identifications Human Pathology Immune Immunosuppressive Agents Individual Infection Inflammation Inflammatory Inflammatory Response Integral Membrane Protein Interferons Lead Leukocytes Ligands Mammals Membrane Proteins Memory Modeling Molecular Mus PECAM1 gene Pathway interactions Peptide/MHC Complex Peripheral Process Production Proteins Publishing Reaction Reagent Recombinants Recruitment Activity Research Resources Rodent SELL gene Screening procedure Signal Transduction Site Surface T memory cell T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TNF gene Tissues Universities allograft rejection antigen processing chemokine cytokine graft failure medical schools migration nectin peripheral blood poliovirus receptor prevent receptor response shear stress therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed research is to identify a receptor for human PECAM-1 that can potentially be targeted by therapeutics to treat human graft rejection. This application proposes to screen an array of more than 2000 human surface proteins using PECAM-1 as a probe. The array was very recently developed by Dr. Lieping Chen, a colleague at Yale University School of Medicine and a collaborator on this project. It represents a very powerful resource not previously available to identify human receptors/counter- receptors. Human endothelial cells (EC) act as antigen presenting cells and affect the recruitment of T cells, an event relevant not only for graft rejection, but potentially or a wide range of human pathologies in which an immune component is implicated (e.g., autoimmune diseases and atherosclerosis). Interestingly, only a small subset of T cells found in the peripheral blood of normal individuals, namely effector memory T cells, are recruited by a distinct mechanism when their TCR is activated by polyclonal TCR- stimulating reagents presented on the surface of the EC. These findings coincide with an emerging paradigm that antigen-specific (or graft-specific) T cells serve as pioneers in an immune reaction. In this paradigm, a small number of antigen-specific T cells are recruited to the site of infection (or a graft) and condition the site via inflammatory cytokines (TNF and IFN-¿) for a cascade of other immune cells. PECAM-1 on the EC is necessary for the recruitment of EM CD4+ T cells in a model mimicking antigen-specific transendothelial migration, yet none of the known receptors for PECAM-1 are expressed on EM CD4+ T cells. This receptor, by controlling antigen (graft) - specific recruitment of EM CD4+ T cells, is a potentially effective target for therapeutics. This application proposes to identify that receptor using Dr. Chen's new array. PUBLIC HEALTH RELEVANCE: Alloimmune reactions are a major cause of human graft failure, characterized by a destruction of the graft vasculature. We have found that human endothelial cells, when presenting antigen to T cells under conditions like that of flowing blood, induce their activation and recruitment by a unique mechanism. These studies will illuminate the molecular mechanisms underlying antigen-driven recruitment of T cells and may lead to the development of specific therapies to ameliorate allograft rejection.

描述（由申请人提供）：拟议研究的目标是鉴定人类 PECAM-1 的受体，该受体可能成为治疗人类移植排斥反应的靶标。该申请计划筛选一系列 2000 多种人类表面蛋白。该阵列是由耶鲁大学医学院的同事、该项目的合作者陈列平博士最近开发的，它代表了一种以前无法用于识别人类的非常强大的资源。人内皮细胞 (EC) 充当抗原呈递细胞并影响 T 细胞的募集，这一事件不仅与移植物排斥有关，而且与免疫成分有关的潜在或广泛的人类病理有关。（例如，自身免疫性疾病和动脉粥样硬化），正常个体外周血中只有一小部分 T 细胞（即效应记忆 T 细胞）在 TCR 被激活时通过独特的机制被招募。这些发现与抗原特异性（或移植物特异性）T 细胞作为免疫反应的先驱的新兴范例相一致。特定的 T 细胞被募集到感染部位（或移植物）并通过炎症细胞因子（TNF 和 IFN-¿ ）对于 EC 上的一系列其他免疫细胞来说，对于在模拟抗原特异性跨内皮迁移的模型中招募 EM CD4+ T 细胞是必要的，但 PECAM-1 的已知受体均未在 EM CD4+ 上表达。这种受体通过控制抗原（移植物）——EM CD4+ T 细胞的特异性募集，成为潜在的有效治疗靶标。大批。公共健康相关性：同种免疫反应是人类移植物失败的一个主要原因，其特征是移植物脉管系统的破坏。我们发现，人内皮细胞在血液流动等条件下向 T 细胞呈递抗原时，会诱导其活化并发挥作用。这些研究将阐明抗原驱动 T 细胞募集的分子机制，并可能导致开发改善同种异体移植排斥的特异性疗法。