Regulatory Pathways in Osteoclasts and Immune Cells during Inflammatory Arthritis

炎症性关节炎期间破骨细胞和免疫细胞的调节途径

• 批准号: 8719733
• 负责人: Roberta Faccio
• 金额: $ 35.28万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719733
• 关键词: 1,2-diacylglycerol; Antigens; Arthritis; Attention; Autoantigens; Bone Resorption; Cells; Data; Dendritic Cells; Development; Diglycerides; Disease Progression; Enzymes; Funding; Goals; Homeostasis; Immune; Immune Cell Activation; In Vitro; Inflammatory; Inflammatory Response; Mediating; Mus; Neutrophil Activation; Osteoclasts; Osteolytic; Pharmacotherapy; Phenotype; Phosphatidic Acid; Population; Production; Recruitment Activity; Regulatory Pathway; Resolution; Rheumatoid Arthritis; Role; Serum; Signal Pathway; Signaling Molecule; Symptoms; T-Cell Activation; T-Lymphocyte; Therapeutic; Thick; base; bone; bone loss; bone mass; cytokine; human PLCG2 protein; immune activation; in vivo; neutrophil; novel; novel strategies; novel therapeutic intervention; osteoclastogenesis; protective effect; public health relevance

DESCRIPTION (provided by applicant): During Rheumatoid Arthritis (RA), increased immune cell activation leads to focal bone erosion as well as systemic bone loss, both mediated by osteoclasts (OCs). Dendritic cells (DCs) are critical components of the inflammatory response associated with RA as they are responsible for the activation of T lymphocytes, due to abnormal presentation of self-antigens. Neutrophils can further enhance the inflammatory condition by recruiting more DCs and contribute to local bone erosion by actively secreting inflammatory and pro-osteoclastogenic cytokines. Unfortunately, traditional pharmacotherapy to block the activity of inflammatory cytokines can be inadequate in controlling symptoms and disease progression. Our overall goal is to identify signaling molecules that are critical to modulate the inflammatory and osteolytic components of RA and that may lay the groundwork for novel and more effective therapeutic approaches. We have previously found that PLC?2 is a critical modulator of bone homeostasis and inflammatory responses associated with RA. However, PLC?2 shares high homology with the more ubiquitously expressed PLC?1, thus rendering its specific targeting difficult. Diacylglycerol (DAG) is a downstream product of PLC?2 catalytic activity and data from our group and others indicate that it mediates PLC?2 function in OCs and immune cells. In order to study the role of DAG, we now turned our attention to DGK?, an enzyme that decreases cellular levels of DAG by converting it to phosphatidic acid (PA). Thus, DGK?-deficiency causes accumulation of DAG. Our preliminary data indicate that DGK? is highly expressed in OCs, neutrophils and DCs. We also found that mice lacking DGK? have a substantial osteoporotic phenotype, characterized by reduced trabecular number and thickness and enhanced OC formation and function. Thus, our data indicate that DGK? is a negative modulator of osteoclast activation. Based on this information, our central hypothesis is that DGK?, via modulation of DAG, is a common regulator of bone and immune cells downstream of PLC?2. Thus, we propose to: Specific Aim 1: Investigate the mechanism by which DGK? modulates osteoclast formation and bone resorption in vitro and in vivo. Specific Aim 2: Examine the role of DGK? in development and resolution of serum induced arthritis and its effect on neutrophil activation. Specific Aim 3: Determine the role of DGK? in antigen-induced arthritis and its effect in DC- mediated T cell activation. The goal of this application is to demonstrate the importance of DGK? in the activation and functionality of OCs, neutrophils and DCs as a way to target both the osteolytic and inflammatory components of RA. This novel approach might lay the basis for new therapeutic interventions for RA.

描述（由申请人提供）：在类风湿关节炎（RA）期间，免疫细胞激活增加会导致局灶性骨侵蚀以及全身性骨质流失，均由破骨细胞（OCS）介导。树突状细胞（DC）是与RA相关的炎症反应的关键成分，因为它们是由于自我抗原的异常表现而导致T淋巴细胞激活的。中性粒细胞可以通过募集更多的DC来进一步增强炎症状况，并通过主动分泌炎症和促层造型性细胞因子来促进局部骨侵蚀。不幸的是，阻止炎症细胞因子活性的传统药物疗法在控制症状和疾病进展方面可能不足。我们的总体目标是确定对调节RA的炎症和溶性成分至关重要的信号分子，这可能为新颖，更有效的治疗方法奠定基础。我们以前已经发现PLC？2是骨稳态的关键调节剂和与RA相关的炎症反应。但是，PLC？2与更普遍表达的PLC？1共享高同源性，从而使其具体的靶向很难。二酰基甘油（DAG）是PLC？2催化活性的下游产物和我们组的数据，而其他数据表明它介导了OCS和免疫细胞中的PLC？2功能。为了研究DAG的作用，我们现在将注意力转向DGK？，一种酶，通过将其转化为磷脂酸（PA），从而降低了DAG的细胞水平。因此，DGK？缺陷导致DAG的积累。我们的初步数据表明DGK？在OC，中性粒细胞和DC中高度表达。我们还发现缺乏DGK的小鼠？具有实质性的骨质疏松表型，其特征是小梁数量减少，厚度以及增强的OC形成和功能。因此，我们的数据表明DGK？是破骨细胞激活的负调节剂。基于这些信息，我们的中心假设是通过DAG调制DGK？是PLC下游的骨骼和免疫细胞的常见调节剂。因此，我们建议：特定目标1：研究DGK的机制？在体外和体内调节破骨细胞的形成和骨吸收。特定目标2：检查DGK的作用？血清诱导关节炎的发育和分辨率及其对中性粒细胞激活的影响。特定目标3：确定DGK的作用？在抗原诱导的关节炎及其在DC介导的T细胞激活中的作用。该应用程序的目的是证明DGK的重要性？在OC的激活和功能中，中性粒细胞和DC是靶向RA的溶性和炎症成分的一种方式。这种新颖的方法可能为RA的新治疗干预奠定了基础。