G-PROTEIN PATHWAYS IN THE KIDNEY TRANSPLANT REJECTION

肾移植排斥反应中的 G 蛋白途径

基本信息

批准号：
7486792
负责人：
THOMAS M COFFMAN
金额：
$ 20.84万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7486792
关键词：
Alloantigen Allografting Angiotensin II Receptor Antigen-Presenting Cells Attenuated Biological Assay Cells Coupled DNA Sequence Rearrangement Data Development Dominant-Negative Mutation Family G Protein-Coupled Receptor Signaling G alpha q Protein G-Protein Signaling Pathway G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Genetic Models Graft Rejection Grant Guanosine Triphosphate Phosphohydrolases Immune Immune response In Vitro Individual Inflammation Inflammatory Injury Kidney Kidney Transplantation Ligands Lymphocyte Mediating Mediator of activation protein Modeling Molecular Monomeric GTP-Binding Proteins Numbers Organ Donor Organ Transplantation Pathogenesis Pathway interactions Peptides Physiological Population Process Protein Family Proteins Rho-associated kinase Role Signal Pathway Signal Transduction Signal Transduction Pathway T-Lymphocyte Testing Thromboxane A2 Thromboxane Receptor Transgenes Transgenic Animals Transplantation base cell motility graft function guanine nucleotide binding protein heart allograft isoimmunity macrophage novel programs receptor receptor coupling response rho GTP-Binding Proteins therapeutic target

项目摘要

The contribution of inflammatory mechanisms to the pathogenesis of transplant rejection is the major focus of this program project. Many key inflammatory mediators act through G protein-coupled receptors (GPCRs) that transduce ligand-dependent signals via hetero-trimeric guanine nucleotide-binding proteins (G proteins). During the previous grant period, we showed that two GPCRs, the AT1 receptor for angiotensin II and the TP receptor for thromboxane A2, promote alloimmunity and graft rejection. Based on the similar actions of these Gq-coupled receptors, we hypothesize that allograft rejection is enhanced through distinct GPCR signaling pathways coupled to Gq proteins and to the activation of Rho GTPases and Rho-kinase. Moreover, we suggest that these pathways influence graft function through discrete actions upon the T cell, upon the macrophage/antigen-presenting cell, and upon the allograft itself. We will test this hypothesis using genetic models with inducible activation or inhibition of Gq and Rho-kinase. By modulating Gq and Rho-kinase signaling in models of transplantation generated through the program core, the contributions of these pathways to the pathogenesis of rejection will be precisely defined. Our proposed studies have the following specific aims: 1. To define the capacity of Gq signaling to promote cellular immune responses. 2. To characterize the actions of Gq signaling in organ transplant rejection. 3. To define the interactions between G proteins and Rho-GTPases in immune cells. 4. To identify the cellular mechanisms of action of Rho-kinase in rejection. Because the large family of GPCRs uses only a limited number of G proteins, we posit that G protein signaling pathways that enhance inflammation and graft injury may be useful therapeutic targets whereby the actions of multiple pro-inflammatory ligands could be blocked by targeting a single common pathway.

炎症机制对移植排斥的发病机制的贡献是该计划项目的主要重点。许多关键的炎症介质通过G蛋白偶联受体（GPCR）作用，该受体（GPCR）通过异源三种鸟嘌呤核苷酸结合蛋白（G蛋白）传递配体依赖性信号。在上一个赠款期间，我们显示了两个GPCR，即血管紧张素II的AT1受体和血栓烷A2的TP受体，促进了同种免疫性和移植排斥。基于这些GQ耦合受体的类似作用，我们假设通过不同的GPCR信号来增强同种异体移植的排斥。与GQ蛋白结合的途径以及Rho GTPase和Rho激酶的激活。此外，我们建议这些途径通过对T细胞，巨噬细胞/抗原呈递细胞以及同种异体移植本身的离散作用来影响移植物的功能。我们将使用具有诱导性激活或抑制GQ和Rho-激酶的遗传模型检验该假设。通过调节通过程序核心产生的移植模型中的GQ和Rho-kinase信号传导，将精确定义这些途径对排斥发病机理的贡献。我们提出的研究具有以下特定目的：1。定义GQ信号传导促进细胞免疫反应的能力。 2。表征器官移植排斥反应中GQ信号的作用。 3。定义之间的相互作用免疫细胞中的G蛋白和Rho-GTPase。 4。鉴定Rho-激酶在排斥反应中的作用机理。由于大型GPCR家族仅使用有限数量的G蛋白，因此我们认为G蛋白信号通路增强炎症和移植损伤可能是有用的治疗靶标，在这种靶标中，可以通过靶向单个常见途径来阻止多种促炎配体的作用。