Molecular mechanisms of cytoskeletal rearrangement in rheumatoid arthritis

描述（由申请人提供）： 类风湿性关节炎（RA）是一种自身免疫性疾病，其与滑膜成纤维细胞（SF）的过度增殖和侵袭性增加相关，导致关节损伤。RA中SF细胞转化的机制仍知之甚少。然而，预计改变的肌动蛋白细胞骨架重塑有助于其侵袭性表型。最近，我们发现，从RA患者（RASFs）分离的SF表达水平升高的肌动蛋白细胞骨架调节剂肌动蛋白丝相关蛋白110千道尔顿（AFAP 1）和Abl酪氨酸激酶相比，正常SF，他们能够形成一个复合物。我们建议AFAP 1和Abl的相互作用有助于改变RASF的细胞骨架重排和RA的病理。在第一个具体的目标，我们将检查的分子特性的AFAP 1复合物和分子的后果，从AFAP 1复合物的形成，特别是Abl活性和AFAP 1的能力，结合和交联肌动蛋白。具体目标2利用AFAP 1的Abl结合突变体的敲低和表达来确定AFAP 1-Abl相互作用在RASF的细胞增殖和迁移/侵袭中的功能作用。了解RA中细胞骨架重排的机制对于开发旨在预防关节破坏的新的治疗策略是重要的。 公共卫生相关性： 风湿性关节炎（RA）影响至少1%的人口。目前的疗法仅部分有效，并且非常需要更有效的治疗方法。我们建议确定新的分子机制，调节肌动蛋白细胞骨架重排滑膜成纤维细胞，有助于RA的病理，以确定新的治疗靶点。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an autoimmune disease, which is associated with hyperproliferation and increased invasiveness of synovial fibroblasts (SFs), leading to joint damage. The mechanisms underlying SF cell transformation in RA remain poorly understood. However, it is expected that altered actin cytoskeletal remodeling contributes to their aggressive phenotype. Recently, we found that SFs isolated from RA patients (RASFs) express elevated levels of the actin cytoskeleton regulators actin filament associated protein of 110 kilodalton (AFAP1) and Abl tyrosine kinase compared to normal SFs and that they are able to form a complex. We propose that the interaction of AFAP1 and Abl contributes to the altered cytoskeletal rearrangement of RASFs and to the pathology of RA. In the first specific aim, we will examine the molecular properties of the Abl-AFAP1 complex and the molecular consequences resulting from the Abl-AFAP1 complex formation, particularly Abl activity and the ability of AFAP1 to bind and crosslink actin. Specific aim 2 utilizes knockdown and expression of an Abl binding mutant of AFAP1 to determine the functional effects of the AFAP1-Abl interaction in cell proliferation and migration/invasion of RASFs. It is important to understand the mechanism of the cytoskeletal rearrangement in RA in order to develop new treatment strategies that are designed to prevent joint destruction. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) affects at least 1% of the population. Current therapies are only partially effective, and there is great need for more effective therapeutic approaches. We propose to identify novel molecular mechanisms that regulate the actin cytoskeletal rearrangement in synovial fibroblasts that contribute to the pathology of RA in order to define new therapeutic targets.