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

• 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
• 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

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）：作为反对感染，中性粒细胞或多形核白细胞（PMN）的有力的第一捍卫者，用强有力的抗菌武器消除了病原体。尽管对于保护至关重要，但不受控制的PMN活性会损害宿主组织，并且与包括类风湿关节炎（RA）在内的多种炎症性疾病有关。已经表明，通过FC伽马受体（FCYR）和整联蛋白刺激后，适配器分子SLP-76是体外PMN激活的关键介体。有趣的是，在PMN室内具有靶向SLP-76的靶向损失的小鼠保持杀死细菌菌株的体内菌株，但在局部炎症模型中减少了血管和组织损伤。该建议旨在进一步了解SLP-76和与结构相关的分子SLP-65（BLNK），坐标PMN激活的机制。通过在小鼠中使用靶向的遗传突变，这些研究将研究SLP-76和BLNK协调信号事件如何在体外和体内PMN激活中调节，并确定SLP-76和/或依赖BLNK依赖性PMN功能是否有助于炎症性疾病。从这些研究中获得的信息可以阐明可以进行治疗的新型信号传导靶标，以最大程度地减少PMN激活的病理后果，如炎性关节炎患者所见，而无需损害PMN杀菌功能。 AIM 1：分析以膜靶向SLP-76支持PMN中FCYR和整联蛋白信号传导的能力。 AIM 2：在没有SLP-76同源物BLNK的情况下评估PMN激活。 AIM 3：在没有SLP-76和/或BLNK的情况下，表征血清诱导的关节炎的传播。与公共卫生有关：中性粒细胞是消除感染的免疫系统的重要细胞，但是当其活性不正常时，例如在类风湿关节炎中，可能会导致炎症和组织损害。提出的实验使用小鼠中的基因突变研究活动物中的中性粒细胞调节，其中包括类风湿关节炎疾病模型。这些研究将有助于确定新方法，以最大程度地减少中性粒细胞激活的破坏力，而不会损害其与感染的能力。