Complement Anaphylatoxin Receptors in Inflammation

补充炎症中的过敏毒素受体

基本信息

批准号：
7632247
负责人：
RICK A. WETSEL
金额：
$ 34.21万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7632247
关键词：
Acute Acute-Phase Reaction Address Adult Respiratory Distress Syndrome Allergic Anaphylatoxins Animals Antigens Arginine Asthma Astrocytes Atopic Dermatitis Attention Autoimmune Diseases B-Lymphocytes Bacteremia Bacteria Belief Binding Biological Biological Assay Biological Process Blood Blood Cells Blood Circulation Blood Pressure Bone Marrow Bradykinin Brain C5a anaphylatoxin receptor CD4 Positive T Lymphocytes CD8B1 gene Carboxypeptidase Categories Cavia Cell surface Cells Cellular Infiltration Chronic Cleaved cell Cloning Coagulation Process Communicable Diseases Complement Complement 3a Complement 5a Complement Activation Complement component C4a Cytolysis Data Dendritic Cells Disease Disease model Dose Endothelial Cells Endotoxemia Enzymes Epithelial Cells Excision Extrinsic asthma Family suidae Fc Receptor Fibrin Fibrinolysis Generations Goals Hepatic Hepatocyte Human Hypotension Immune response Immune system Immunity Infection Inflammation Inflammation Mediators Inflammatory Injection of therapeutic agent Injury Institutes Interleukins Intravenous Investigation Kidney Kinins Knock-out Knockout Mice Kupffer Cells Laboratories Leukocytes Listeria monocytogenes Liver Lung Lung Inflammation Lysine Lysine Carboxypeptidase Mediating Mediator of activation protein Membrane Memory Modeling Molecular Molecular Medicine Multiple Organ Failure Mus Myelogenous National Institute of Allergy and Infectious Disease Nature Neurons Pathogenesis Pathway interactions Peptides Peritoneal Peritonitis Physiological Plasma Plasminogen Play Pneumonia Production Property Reagent Regulation Relative (related person)Research Research Activity Rheumatoid Arthritis Role Sepsis Septic Shock Serum Shock Site Skin Spleen System T-Lymphocyte Texas Thioglycolates Thrombin Time Tissues Tubular formation Universities Vascular Smooth Muscle arginyllysine cDNA Probes cell motility chemokine cytokine directional cell fighting in vitro testing in vivo interest intraperitoneal intravenous administration macrophage medical schools monocyte neutrophil novel pathogen prevent programs receptor research study response seven-transmembrane G-protein-coupled receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): One of the major biological consequences of complement activation is the generation of three small cationic peptides C3a, C4a, and C5a, collectively referred to as complement anaphylatoxins. The complement anaphylatoxins mediate numerous biological functions by binding to seven transmembrane G-protein coupled receptors expressed on specific target cells. The acute and chronic overproduction of the two most potent anaphylatoxins, C3a and C5a, is considered to be a major contributor to the pathogenesis of numerous diseases, including rheumatoid arthritis, sepsis, tissue ischemic injury, acute respiratory distress syndrome, multiple system organ failure, and atopic asthma. The complement anaphylatoxins are regulated by carboxypeptidases, which generate their much less active desArg derivatives, C3adesArg and C5adesArg. Historically, CPN, the carboxypeptidase expressed constitutively in plasma, was thought to be the sole carboxypeptidase regulator of complement anaphylatoxins. Recently, two other carboxypeptidases, CPR and CPM, which are expressed in the serum and on epithelial cells (lung and kidney), respectively, have been proposed as additional carboxypeptidase regulators of C3a and C5a. During the past few years studies in our laboratory as well as in others have revealed that the complement anaphylatoxins C3a and C5a in addition to their traditional phlogistic properties are significant modulators of CD4+ Th1 and Th2 effector functions in allergic and infectious disease. The goal of this research program is to increase our understanding of the regulation and biological functions that the complement anaphylatoxins and their receptors mediate in inflammation, immunity, and T cell responses in relevant infectious diseases. By employing C3aR, C5aR, CPN, and CPM "knock-out" mice generated in our laboratory, we propose to major goals: 1) to delineate and evaluate the overall physiological significance of CPN, CPR, and CPM in regulating biological responses mediated by C3a, C5a, bradykinin, and other important inflammatory molecules, and 2) delineate cellular interactions and molecular mechanisms by which the complement anaphylatoxin receptors, C3aR and C5aR/CD88 modulate T-cell effector functions, which are important in the pathogenesis of Listeria monocytogenes.

描述（由申请人提供）：补体激活的主要生物学后果之一是产生三种小阳离子肽C3A，C4A和C5A，共同称为补体过敏毒素。补体过敏毒素通过与在特定靶细胞上表达的七个跨膜G蛋白偶联受体结合来介导许多生物学功能。两种最有效的过敏毒素C3A和C5A的急性和慢性过量产生被认为是多种疾病的发病机理的主要因素，包括类风湿关节炎，脓毒症，浸润性局部缺血性损伤，急性呼吸困扰综合征，急性呼吸窘迫综合征，多系统器官失败，以及ATOPIC ASTHMA。补体过敏毒素受羧肽酶的调节，羧肽酶会产生其活性较低的DESARG衍生物，C3ADESARG和C5ADESARG。从历史上看，CPN是在血浆中组成型表达的羧肽酶，被认为是补体过敏毒素的唯一羧肽酶调节剂。最近，已经提出了另外两种羧肽酶CPR和CPM，分别在血清和上皮细胞（肺和肾脏）上表达为C3A和C5A的附加羧肽酶调节剂。在过去的几年中，我们的实验室以及其他研究表明，除了传统的Phlogistic特性外，补体过敏毒素C3A和C5A是CD4+ TH1和TH2效应子在过敏和感染性疾病中的重要调节剂。该研究计划的目的是提高我们对相关感染性疾病中过敏毒素及其受体在炎症，免疫力和T细胞反应中介导的调节和生物学功能的理解。通过使用我们实验室中产生的C3AR，C5AR，CPN和CPM“敲除”小鼠，我们提出了主要目标：1）在调节CPN，CPR和CPM的整体生理意义上，在调节由C3A，C5A，C5A，Bradyseled和其他重要的脑部和其他分类的CPN和CPM调节生物学反应中的整体生理意义，并补体过敏毒素受体，C3AR和C5AR/CD88调节T细胞效应子功能的分子机制，在单核细胞增生李斯特菌的发病机理中很重要。