The adaptor molecule SLP-76 in neutrophil functions and inflammatory disease

接头分子SLP-76在中性粒细胞功能和炎症性疾病中的作用

基本信息

批准号：
7498023
负责人：
Laurie Lenox
金额：
$ 5.89万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7498023
关键词：
76-kDa SH2 domain-containing leukocyte protein Activities of Daily Living Adaptor Signaling Protein Adverse effects Animals Antigen Receptors Arthritis B cell linker protein B-Lymphocytes BLNK gene Bacteria Biochemical Blood Vessels Cell membrane Cells Complex Cytosol Disease Disease model Distal Event Exhibits Family Financial compensation Gene Mutation Genetic Homologous Gene ITAM IgG Receptors Immune system In Vitro Infection Inflammation Inflammatory Integrins K/BxN model Kinetics LCP2 gene Laboratories Leukocytes Life Link Localized Mediator of activation protein Membrane Membrane Microdomains Modeling Mouse Strains Movement Mus Mutation Myelogenous Myeloid Cells Neutrophil Activation Numbers Pathogenesis Pathway interactions Patients Phenotype Property Proteins Public Health Regulation Rheumatoid Arthritis Role Serum Shwartzman Phenomenon Signal Pathway Signal Transduction Staphylococcus aureus Tissues Wild Type Mouse analog antimicrobial bactericide design fighting immunoglobulin receptor in vivo in vivo Model killings leukocyte activation member migration mouse model mutant neutrophil novel pathogen prevent receptor research study response

项目摘要

DESCRIPTION (provided by applicant): As potent first defenders against infection, neutrophils, or polymorphonuclear leukocytes (PMN), eliminate pathogens with a powerful repertoire of antimicrobial weapons. Although essential for protection, uncontrolled PMN activity damages host tissues and is associated with a number of inflammatory diseases including rheumatoid arthritis (RA). It has been shown that the adaptor molecule SLP-76 is a critical mediator of in vitro PMN activation following stimulation through Fc gamma receptors (FcyR) and integrins. Interestingly, mice with targeted loss of SLP-76 within the PMN compartment maintain the ability to kill the bacterial strain S. Aureus in vivo, but have reduced vascular and tissue damage in a model of localized inflammation. This proposal is designed to further understand the mechanisms by which SLP-76 and the structurally related molecule SLP-65 (BLNK), coordinate PMN activation. Through the use of targeted genetic mutations in mice, these studies will examine how SLP-76 and BLNK coordinate signaling events regulating in vitro and in vivo PMN activation, and determine whether SLP-76 and/or BLNK-dependent PMN functions contribute to inflammatory disease. Information gained from these studies may elucidate novel signaling targets that can be therapeutically manipulated in order to minimize the pathological consequences of PMN activation, as seen in patients with inflammatory arthritis, without compromising PMN bactericidal capabilities. Aim 1: Analyze the ability of membrane-targeted SLP-76 to support FcyR and integrin signaling in PMN. Aim 2: Evaluate PMN activation in the absence of the SLP-76 homologue BLNK. Aim 3: Characterize the propagation of serum-induced arthritis in the absence of SLP-76 and/or BLNK. Relevance to Public Health: Neutrophils are an essential cell of our immune system that eliminate infections, but can contribute to inflammation and tissue damage when their activity is misregulated, such as in rheumatoid arthritis. The proposed experiments use genetic mutations in mice to study neutrophil regulation in a live animal, which includes a disease model of rheumatoid arthritis. These studies will help identify new ways to minimize the destructive forces of neutrophil activation, without compromising their ability to fight infections.

描述（由申请人提供）：作为对抗感染、中性粒细胞或多形核白细胞 (PMN) 的有力第一防御者，利用强大的抗菌武器消灭病原体。虽然中性粒细胞的活性对于保护至关重要，但不受控制的中性粒细胞活性会损害宿主组织，并与包括类风湿性关节炎 (RA) 在内的多种炎症性疾病相关。研究表明，接头分子 SLP-76 是 Fc γ 受体 (FcyR) 和整合素刺激后体外 PMN 激活的关键介质。有趣的是，在 PMN 区室中靶向丢失 SLP-76 的小鼠保持了体内杀死金黄色葡萄球菌菌株的能力，但在局部炎症模型中减少了血管和组织损伤。该提案旨在进一步了解 SLP-76 和结构相关分子 SLP-65 (BLNK) 协调 PMN 激活的机制。通过在小鼠中使用靶向基因突变，这些研究将检查 SLP-76 和 BLNK 如何协调调节体外和体内 PMN 激活的信号事件，并确定 SLP-76 和/或 BLNK 依赖的 PMN 功能是否导致炎症性疾病。从这些研究中获得的信息可能会阐明新的信号传导目标，这些信号传导目标可以通过治疗手段进行操作，以最大限度地减少中性粒细胞激活的病理后果（如炎症性关节炎患者中所见），同时又不影响中性粒细胞的杀菌能力。目标 1：分析膜靶向 SLP-76 支持 PMN 中 FcyR 和整合素信号传导的能力。目标 2：在不存在 SLP-76 同源物 BLNK 的情况下评估 PMN 激活。目标 3：表征在不存在 SLP-76 和/或 BLNK 的情况下血清诱导的关节炎的传播。与公共健康的相关性：中性粒细胞是我们免疫系统的重要细胞，可以消除感染，但当其活性调节不当时，例如在类风湿性关节炎中，可能会导致炎症和组织损伤。拟议的实验利用小鼠的基因突变来研究活体动物的中性粒细胞调节，其中包括类风湿性关节炎的疾病模型。这些研究将有助于找到新的方法，以最大限度地减少中性粒细胞激活的破坏力，而不损害其抵抗感染的能力。