Mac-1 (CR3) and Fc gamma receptors in immune-mediated neutrophil cytotoxicity

Mac-1 (CR3) 和 Fc gamma 受体在免疫介导的中性粒细胞细胞毒性中的作用

基本信息

批准号：
8423361
负责人：
Tanya N Mayadas
金额：
$ 35.94万
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：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423361
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Adhesives Antibodies Antigen-Antibody Complex Attenuated Autoimmune Diseases Autoimmune Process Autoimmune hemolytic anemia Binding Biochemical Biological Assay Bullous Pemphigoid C3bi Clinical Trials Complement Coupled Cutaneous Involvement Data Deposition Dermal Disease Ensure Erythrocytes Exhibits Family Family member Funding Generations Glomerulonephritis Glucans Goals Grant Guanine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Hemolytic Anemia Hemorrhagic Vasculitis Host Defense Host Defense Mechanism ITAM IgG Receptors Immune Immunity Immunocompromised Host Immunoglobulin G Immunosuppression In Vitro Infection Inflammatory Inflammatory Response Injury Integrins Lead Leukocyte Elastase Link Macrophage-1 Antigen Mediating Modeling Molecular Mycoses Myelogenous NADPH Oxidase Neutrophil Infiltration Organ PTK2 gene Pathology Pathway interactions Phagocytes Phagocytosis Phagosomes Pharmaceutical Preparations Phospholipase C Phospholipase D Phosphorylation Phosphotransferases Physiological Play Predisposition Process Protein Family Protein Kinase C Protein Tyrosine Kinase Proteins Proteomics Reactive Oxygen Species Regulation Relative (related person)Respiratory Burst Rheumatism Role Shwartzman Phenomenon Signal Pathway Signal Transduction Signaling Molecule Therapeutic Tissues Transducers Treatment Efficacy Variant Vasculitis base combat comparative cytotoxic cytotoxicity dectin 1 design glomerular basement membrane human SYK protein human disease in vitro Assay in vivo in vivo Model interest macrophage microbial natalizumab neutrophil neutrophil cytosol factor 40K opsonin receptor particle protein function public health relevance rac GTP-Binding Proteins receptor response rho rho GTP-Binding Proteins skin disorder src-Family Kinases therapeutic development therapeutic target tool trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): Phagocytic functions of neutrophils and macrophages are essential for immunity to microbial infection, but can also contribute to tissue injury during inflammatory responses and autoimmune pathologies. The overall goal of this application is to continue to extend our understanding of the molecular basis of phagocyte cytotoxicity focusing on two major opsonic receptors on phagocytes, Fc?Rs (receptors for IgG immune complex) and the ¿2 integrin Mac-1 (receptor for complement fragment iC3b). Major accomplishments of the past 4 years were to 1) demonstrate that Vav proteins, exchange factor for Rho GTPase family members are required for several Mac-1 and Fc?R mediated adhesive functions in neutrophils, 2) identify Vav proteins as the major signal transducers of NADPH oxidase activation following Fc?R engagement, through regulation of Rac GTPases and phosphorylation of the NADPH oxidase p40phox, 3) present in vivo evidence that neutrophil Fc?R dependent but not complement dependent tissue injury requires Vav and Rac proteins, 4) define a role for Mac-1 in triggering neutrophil elastase release and subsequent hemorrhagic vasculitis in vivo, through activation of the src and syk kinases, and 5) demonstrate a critical role for Mac-1 on neutrophils in two additional complement dependent models, bullous pemphigoid and thrombotic glomerulonephritis. The current application builds on these discoveries. The objective of Aim I is to delineate mechanisms of neutrophil phagocytosis that are relevant for complement C3 mediated tissue injury and host defense. In particular we will examine both signals that lead to Mac-1 binding of its target and those that link Mac-1 to downstream effector functions. In Aim II, we will further delineate mechanisms of Vav mediated regulation of the NADPH oxidase following Fc?R engagement in neutrophils and macrophages. We will also clarify the role of Vav and Rac in IgG or complement mediated phagocytosis in macrophages in models of autoimmune hemolytic anemia. We anticipate that the completion of our aims should lead to a better understanding of signaling pathways that link opsonic receptors to specific phagocyte cytotoxic functions. This may aid in the design of therapeutics to selectively target pathways responsible for tissue damage in inflammatory and autoimmune disorders while minimizing effects on host defense.

描述（由申请人提供）：中性粒细胞和巨噬细胞的吞噬功能对于微生物感染的免疫至关重要，但也可能导致炎症反应和自身免疫病理过程中的组织损伤。本申请的总体目标是继续扩展我们对微生物感染的理解。吞噬细胞细胞毒性的分子基础，重点关注吞噬细胞上的两种主要调理受体：Fc?R（IgG 免疫复合物的受体）和 ¿ 2 整合素 Mac-1（补体片段 iC3b 的受体）过去 4 年的主要成就是 1) 证明 Vav 蛋白（Rho GTPase 家族成员的交换因子）是多种 Mac-1 和 Fc?R 介导的粘附功能所必需的。在中性粒细胞中，2) 通过调节 Rac GTPases 和 Fc?R 接合，确定 Vav 蛋白是 Fc?R 参与后 NADPH 氧化酶激活的主要信号转导子NADPH 氧化酶 p40phox 的磷酸化，3) 体内证据表明中性粒细胞 Fc?R 依赖性而非补体依赖性组织损伤需要 Vav 和 Rac 蛋白，4) 定义了 Mac-1 在触发中性粒细胞弹性蛋白酶释放和随后的出血性血管炎中的作用体内，通过激活 src 和 syk 激酶，5) 证明 Mac-1 对中性粒细胞的关键作用两个额外的补体依赖性模型，大疱性类天疱疮和血栓性肾小球肾炎当前的应用建立在这些发现的基础上，目的是描述与补体 C3 介导的组织损伤和宿主防御相关的中性粒细胞吞噬机制。导致 Mac-1 与其靶标结合的信号以及将 Mac-1 与下游效应器功能联系起来的信号。在 Aim II 中，我们将进一步描述 Vav 的机制。我们还将阐明 Vav 和 Rac 在自身免疫性溶血性贫血模型中巨噬细胞中 IgG 或补体介导的吞噬作用中的作用。导致更好地理解将调理受体与特定吞噬细胞细胞毒性功能联系起来的信号通路，这可能有助于设计选择性靶向通路的治疗方法。负责炎症和自身免疫性疾病中的组织损伤，同时最大限度地减少对宿主防御的影响。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia.

补体成分 C3 和补体受体 3 型有助于小胶质细胞对纤维状 Aβ 的吞噬和清除。

DOI：
发表时间：
2012-05
期刊：
影响因子：
6.2
作者：
Fu, Hongjun;Liu, Bin;Frost, Jeffrey L;Hong, Soyon;Jin, Ming;Ostaszewski, Beth;Shankar, Ganesh M;Costantino, Isabel M;Carroll, Michael C;Mayadas, Tanya N;Lemere, Cynthia A
通讯作者：
Lemere, Cynthia A