SHPS-1 As a Regulator of Innate Immunity in Arthritis

SHPS-1 作为关节炎先天免疫的调节剂

• 批准号: 6949037
• 负责人: William E Seaman
• 金额: $ 16.5万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6949037
• 关键词: cell cell interaction; differentiation antigens; disease /disorder model; immunity; immunologic receptors; laboratory mouse; lymphocyte; macrophage; monoclonal antibody; rheumatoid arthritis

DESCRIPTION (provided by applicant): This R21 application is in response to a Request for Proposals for studies that will develop an "understanding of the role of innate immunity in the etiopathogenesis of autoimmune rheumatic diseases," with particular relevance to an understanding of "the earlier events of the etiopathogenesis of disease." To this end, we have united two new approaches. The molecular focus of our studies is SHPS-1, a regulatory receptor that is expressed primarily on cells of macrophage lineage. SHPS-1 regulates the activation of innate immunity and the consequent activation of adaptive immunity, as well as leukocyte migration and the formation of osteoclasts from macrophages. Thus, SHPS-1 has the potential to regulate the interactions between the innate immune system (macrophages) and adaptive immunity (lymphocytes) at many points in the development of autoimmunity, but its role in autoimmunity has not previously been studied. We propose to do so through the study of a new mouse model for rheumatoid arthritis, SKG mice, in which the development of arthritis is heavily dependent on activation of the innate immune system. Our goal is to develop and characterize 3 models in which the role of SHPS-1 in the RA-like disease of SKG mice can be studied. These are: 1. SKG mice treated in vivo with a blocking monoclonal antibody to SHPS-1. 2. SKG mice in which SHPS-1 lacks the cytoplasmic domain. 3. SKG mice in which SHPS-1 is not expressed at all. If these models support a role of SHPS-1 in the regulation of arthritis, they will provide excellent models to dissect the cellular interactions that elicit the RA-like disease in SKG mice. Because SHPS-1 has a close homologue in humans (SIRPal), the results may have direct application to patients with RA.

描述（由申请人提供）： 这项R21申请是对一项研究提案的回应，该研究将发展“对先天免疫在自身免疫性风湿性疾病发病机制中的作用的理解”，特别是与理解“疾病发病机制的早期事件”相关。“为此，我们结合了两种新方法。我们研究的分子焦点是SHPS-1，一种主要在巨噬细胞谱系细胞上表达的调节受体。SHPS-1调节先天免疫的激活和随后的适应性免疫的激活，以及白细胞迁移和从巨噬细胞形成破骨细胞。因此，SHPS-1有可能在自身免疫发展的许多点上调节先天免疫系统（巨噬细胞）和适应性免疫（淋巴细胞）之间的相互作用，但其在自身免疫中的作用以前尚未研究过。我们建议通过研究一种新的类风湿性关节炎小鼠模型SKG小鼠来做到这一点，其中关节炎的发展在很大程度上依赖于先天免疫系统的激活。我们的目标是开发和表征3种模型，其中可以研究SHPS-1在SKG小鼠RA样疾病中的作用。这些是： 1.用SHPS-1的阻断性单克隆抗体在体内治疗的SKG小鼠。 2. SHPS-1缺乏胞质结构域的SKG小鼠。 3. SKG小鼠，其中SHPS-1根本不表达。 如果这些模型支持SHPS-1在关节炎调节中的作用，它们将提供极好的模型来剖析引起SKG小鼠RA样疾病的细胞相互作用。由于SHPS-1在人类中有一个密切的同源物（SIRP），因此该结果可能直接应用于RA患者。