权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of complement induced endothelial dysfunction

补体诱导内皮功能障碍的机制

基本信息

批准号：
7225277
负责人：
GREGORY L STAHL
金额：
$ 33.24万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7225277
关键词：
Abbreviations Acetylglucosamine Affinity Anaphylatoxin Anaphylatoxins Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Binding C3bi C5a anaphylatoxin receptor Complement Complement 3a Complement 5a Complement Activation Complement Factor D Complement Membrane Attack Complex Complement component C5 Complex Data Deposition Endothelial Cells Endothelium Functional disorder Funding Gene Expression Gene Expression Profile Genes Human Hypoxia Immunoglobulin M In Vitro Inflammation Inflammatory Injury Ischemia Knockout Mice Knowledge Laboratories Lectin Literature Lung Mannose Binding Lectin Mannose-Binding Lectin Complement Pathway Mannose-Binding Lectins Mediating Micro Array Data Modeling Molecular Monoclonal Antibodies Mus Organ Oxidative Stress Pathogenesis Pathway interactions Physiological reperfusion Play Polymerase Chain Reaction Proteins Publications Rattus Reagent Recombinants Regulation Reperfusion Injury Reperfusion Therapy Reporting Research Research Personnel Resolution Reverse Transcriptase Polymerase Chain Reaction Role Serine Protease Serum Staging Stress Structure Surface Plasmon Resonance Thinking Time Tissues Umbilical vein Upper arm Vascular Endothelial Cell Wing cobra venom factor complement pathway defined contribution esterase inhibitor gastrointestinal human data ileum in vivo mouse model neutrophil novel novel therapeutics programs restoration therapeutic target

项目摘要

DESCRIPTION (provided by applicant): While the exact mechanisms of ischemia/reperfusion injury remain to be elucidated, inhibition of complement activation (e.g., sCRl or Cl esterase inhibitor), depletion of complement components (e.g., cobra venom factor) and complement component (e.g., C3 and C4) knockout mice have revealed an important role of complement in ischemia/reperfusion (I/R) injury. During the previous two funding cycles we have shown that complement is activated on human endothelial cells following oxidative stress and involves the activation of the lectin complement pathway and mannose binding lectin (MBL). During the last cycle, we identifed C5 as a critical complement component involved in gastrointestinal (G) I/R injury. However, the specific pathways involved, the order of pathway activation, and the specific contribution of C5a versus C5b-9 in the setting of GI/R is not well characterized. Reports in the literature suggest that the classical pathway initiates complement activation and mediates tissue injury in GI/R by way of natural antibody (IgM) deposition. Our preliminary data demonstrate complement activation in GI/R is Clq-independent. Preliminary data raise a new potential role for IgM and MBL interactions, perhaps setting stage for a new paradigm in complement activation. This application will investigate the several gaps in our knowledge about complement and its role in mediating tissue injury and inflammation associated with GI/R. Novel anti-complement reagents and knockout mice have been developed for characterizing the role of each complement pathway in GI/R. Specifically we will identify the importance of each specific complement pathway (e.g., lectin, classical and alternative) in GI/R. Previous reports by our group and others have demonstrated that complement activation influences gene expression and we will identify novel pro- and anti-inflammatory genes that are regulated by complement activation and define the role of C5a vs C5b-9 in GI/R, which seems to differ in the ileum compared to other organs. Novel and potential therapeutically useful reagents will be made and used in vivo to establish and validate the genes expressed in vivo and resolution of inflammation in vivo. Our aims are to: 1) Characterize complement pathways involved in complement activation GI/R; 2) define the role of CSa, C3a and C5b-9 in GI/R, 3) characterize the role of MASPs, IgM and MBL complex regulation in GI/R and oxidatively stressed endothelium, and 4) Define/validate the gene expression profile of the lung and ileum following I/R with an emphasis on complement dependent and independent mechansims.

描述（由申请人提供）：