HOMEOSTATIC CONTROL OF MACROPHAGE FC-GAMMA RECEPTOR FUNCTION

巨噬细胞 FC-γ 受体功能的稳态控制

基本信息

批准号：
7313940
负责人：
Susheela Tridandapani
金额：
$ 22.25万
依托单位：
OHIO STATE 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：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7313940
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one 70-kDa Ribosomal Protein S6 Kinases Actins Anti-Inflammatory Agents Anti-inflammatory Antibodies Antibody Therapy Antigen-Antibody Complex Applications Grants Attention B-Cell Lymphomas Biochemistry Biological Process Biology Cancer Patient Cell Line Cell model Cells Cellular Immunity Cellular biology Clinical Collaborations Complex Cytochromes Cytokine Gene Defense Mechanisms Disease Dominant-Negative Mutation Effector Cell Event Fc Receptor Funding GTP Binding Gene Expression Generations Genetic Transcription Health Human IgG Receptors Immunoglobulin G Immunologic Receptors Immunology Immunotherapeutic agent Immunotherapy Individual Inflammation Inflammatory Interleukin-10 Interleukin-12 Interleukin-4 Interleukin-6 Investigation Lead Link Lymphocyte MAPK8 gene Macrophage Activation Malignant Neoplasms Mediating Mediator of activation protein Membrane Microscopy Modeling Molecular Molecular Biology Monoclonal Antibodies Monokines Mus Myelogenous NADPH Oxidase Natural Killer Cells Nitrogen Normal Cell Oligonucleotides Oxygen Patients Phagocytosis Phosphoric Monoester Hydrolases Phosphorylation Play Process Production Protein Overexpression Protein-Serine-Threonine Kinases Proteins Reactive Oxygen Species Recruitment Activity Regulation Reporting Research Research Personnel Role Signal Pathway Signal Transduction Site Small Interfering RNA Stimulus Surface System T-Lymphocyte Techniques Testing Therapeutic Tissues Transcription Factor AP-1 Transforming Growth Factor beta Transgenic Animals Tumor Antibodies Work antibody-dependent cell cytotoxicity base cancer therapy cell type cytokine functional outcomes human MAPK14 protein in vivo interleukin-17C interleukin-21 macrophage malignant breast neoplasm mitogen-activated protein kinase p38 monocyte multidisciplinary mutant neoplastic cell neutralizing antibody novel novel therapeutics peripheral blood polymerization programs protein expression receptor receptor expression receptor function research study response tool transcription factor tumor

项目摘要

The long-term objective of this project is to understand the regulation of FcgammaR-mediated functions such as phagocytosis and ADCC, both important defense mechanisms in cancer. Antibodies form an important link between humoral and cell-mediated immunity. The Fc region of the antigen-complexed antibody serves to activate FcR-bearing effector cells to antigenic challenge. Indeed this basic principle has been elegantly exploited by cancer biologists to develop antibody-mediated therapeutic approaches. In murine models of antibody therapy, it has been clearly demonstrated that anti-tumor antibodies work by recruiting and activating Fc receptor-bearing effector cells, predominantly monocytes/macrophages, leading to the destruction of the tumor cells. Thus, it is critical to understand the molecular details of macrophage FcgammaR expression and function to develop strategies to enhance the efficacy of anti-tumor antibodies. Our work in the last several years has revealed two critical findings, i.e that Fc receptor-mediated macrophage functions are critically regulated by phosphatases through their influence on Akt, and that the expression of the activating and the inhibiting Fc receptors is differentially regulated by mediators present in the surrounding milieu leading to altered functional outcomes. Thus in the current grant proposal we propose the following three specific aims: 1) to examine the unexpected role of Akt on Fcgamma receptor- mediated macrophage activation events leading to phagocytosis and ADCC against antibody-coated tumor cells, 2) to examine the influence of Akt on phagocytosis-associated inflammatory events such as cytokine production and the generation of reactive oxygen species, and 3) to investigate the influnec of TGFbeta and CpG ODN on Fcgamma receptor expression and function. A thorough understanding of monocyte/macrophage Fcgamma receptor expression and function will likely identify better immunotherapeutic strategies to enhance the efficacy of monoclonal antibodies in cancer therapy. Given our interactions with the other Projects and the Cores of this Program Project, we are optimally poised to unravel the molecular details of monocyte/macrophage biology as it pertains to Fc receptor-mediated functional outcomes.

该项目的长期目标是了解FCGAMMAR介导的功能的调节例如吞噬作用和ADCC，都是癌症的重要防御机制。抗体形成体液和细胞介导的免疫力之间的重要联系。抗原复合的FC区域抗体可激活含有FCR的效应细胞抗原挑战。的确，这个基本原则已经癌症生物学家优雅地利用了抗体介导的治疗方法。在抗体疗法的鼠模型，已经清楚地证明了抗肿瘤抗体可通过募集和激活FC受体效应细胞，主要是单核细胞/巨噬细胞，领先破坏肿瘤细胞。因此，了解巨噬细胞的分子细节至关重要 FCGAMMAR表达和功能以开发策略以增强抗肿瘤抗体的功效。过去几年我们的工作揭示了两个关键发现，即FC受体介导巨噬细胞功能受磷酸酶对AKT的影响严重调节，并且激活和抑制FC受体的表达受到存在于周围的环境导致功能结果改变。因此，在当前的赠款建议中我们提出以下三个特定目标：1）检查AKT在Fcgamma受体中的意外作用介导的巨噬细胞激活事件导致吞噬作用和针对抗体涂层肿瘤的ADCC 细胞，2）检查Akt对吞噬作用相关的炎症事件（例如细胞因子）的影响生产和活性氧的产生，以及3）研究TGFBETA和 FCGAMMA受体表达和功能上的CpG ODN。对单核细胞/巨噬细胞FCGAMMA受体表达和功能的透彻理解可能会确定更好的免疫治疗策略来增强单克隆抗体在癌症中的功效治疗。鉴于我们与该计划项目的其他项目和核心的互动，我们是最佳地阐明了与FC有关的单核细胞/巨噬细胞生物学的分子细节受体介导的功能结果。